Process of preparing 2-thiopyrimidine aldehyde

ABSTRACT

Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.

This is a divisional of application Ser. No.: 08/819,619, filed Mar. 17,1997 (now U.S. Pat. No. 6,103,936) which is a divisional application ofU.S. Ser. No. 08/702,250, filed Aug. 21, 1996 (now U.S. Pat. No.5,663,334) which is a continuation of 08/472,366 filed Jun. 7, 1995 (nowU.S. Pat. No. 5,593,992) which is a CIP of 08/369,964 filed Jan. 9, 1995which is a CIP of PCT/US94/07969, filed Jul. 15, 1994 which is a CIP of08/092,733 filed Jul. 16, 1993 (now abandoned).

This invention relates to a novel group of imidazole compounds,processes for the preparation thereof, the use thereof in treatingcytokine mediated diseases and pharmaceutical compositions for use insuch therapy.

BACKGROUND OF THE INVENTION

Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biologicalsubstances produced by a variety of cells, such as monocytes ormacrophages. IL-1 has been demonstrated to mediate a variety ofbiological activities thought to be important in immunoregulation andother physiological conditions such as inflammation [See, e.g.,Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. The myriad ofknown biological activities of IL-1 include the activation of T helpercells, induction of fever, stimulation of prostaglandin or collagenaseproduction, neutrophil chemotaxis, induction of acute phase proteins andthe suppression of plasma iron levels.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis, osteoarthritis, endotoxemia and/ortoxic shock syndrome, other acute or chronic inflammatory disease statessuch as the inflammatory reaction induced by endotoxin or inflammatorybowel disease; tuberculosis, atherosclerosis, muscle degeneration,cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis,gout, traumatic arthritis, rubella arthritis, and acute synovitis.Recent evidence also links IL-1 activity to diabetes and pancreatic βcells.

Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985), reviews thebiological activities which have been attributed to IL-1. It should benoted that some of these effects have been described by others asindirect effects of IL-1.

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions; sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusioninjury, graft vs. host reaction, allograft rejections, fever andmyalgias due to infection, such as influenza, cachexia secondary toinfection or malignancy, cachexia, secondary to acquired immunedeficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloidformation, scar tissue formation, Crohn's disease, ulcerative colitis,or pyresis.

AIDS results from the infection of T lymphocytes with HumanImmunodeficiency Virus (HIV). At least three types or strains of HIVhave been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence ofHIV infection, T-cell mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms. HIV entry into the T lymphocyte requires T lymphocyteactivation. Other viruses, such as HIV-1, HIV-2 infect T lymphocytesafter T Cell activation and such virus protein expression and/orreplication is mediated or maintained by such T cell activation. Once anactivated T lymphocyte is infected with HIV, the T lymphocyte mustcontinue to be maintained in an activated state to permit HIV geneexpression and/or HIV replication. Monokines, specifically TNF, areimplicated in activated T-cell mediated HIV protein expression and/orvirus replication by playing a role in maintaining T lymphocyteactivation. Therefore, interference with monokine activity such as byinhibition of monokine production, notably TNF, in an HIV-infectedindividual aids in limiting the maintenance of T cell activation,thereby reducing the progression of HIV infectivity to previouslyuninfected cells which results in a slowing or elimination of theprogression of immune dysfunction caused by HIV infection. Monocytes,macrophages, and related cells, such as kupffer and glial cells, havealso been implicated in maintenance of the HIV infection. These cells,like T-cells, are targets for viral replication and the level of viralreplication is dependent upon the activation state of the cells. [SeeRosenberg et al., The Immunopathogenesis of HIV Infection, Advances inImmunology, Vol. 57, (1989)]. Monokines, such as TNF, have been shown toactivate HIV replication in monocytes and/or macrophages [See Poli, etal., Proc. Natl. Acad. Sci., 87:782-784 (1990)], therefore, inhibitionof monokine production or activity aids in limiting HIV progression asstated above for T-cells.

TNF has also been implicated in various roles with other viralinfections, such as the cytomegalia virus (CMV), influenza virus, andthe herpes virus for similar reasons as those noted.

Interleukin-8 (IL-8) is a chemotactic factor first identified andcharacterized in 1987. IL-8 is produced by several cell types includingmononuclear cells, fibroblasts, endothelial cells, and keratinocytes.Its production from endothelial cells is induced by IL-1, TNF, orlipopolysachharide (LPS). Human IL-8 has been shown to act on Mouse,Guinea Pig, Rat, and Rabbit Neutrophils. Many different names have beenapplied to IL-8, such as neutrophil attractant/activation protein-1(NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF),neutrophil activating factor (NAF), and T-cell lymphocyte chemotacticfactor.

IL-8 stimulates a number of functions in vitro. It has been shown tohave chemoattractant properties for neutrophils, T-lymphocytes, andbasophils. In addition it induces histamine release from basophils fromboth normal and atopic individuals as well as lysozomal enzyme releaseand respiratory burst from neutrophils. IL-8 has also been shown toincrease the surface expression of Mac-1 (CD11b/CD18) on neutrophilswithout de novo protein synthesis, this may contribute to increasedadhesion of the neutrophils to vascular endothelial cells. Many diseasesare characterized by massive neutrophil infiltration. Conditionsassociated with an increased in IL-8 production (which is responsiblefor chemotaxis of neutrophil into the inflammatory site) would benefitby compounds which are suppressive of IL-8 production.

IL-1 and TNF affect a wide variety of cells and tissues and thesecytokines as well as other leukocyte derived cytokines are important andcritical inflammatory mediators of a wide variety of disease states andconditions. The inhibition of these cytokines is of benefit incontrolling, reducing and alleviating many of these disease states.

There remains a need for treatment, in this field, for compounds whichare cytokine suppressive anti-inflammatory drugs, i.e. compounds whichare capable of inhibiting cytokines, such as IL-1, IL-6, IL-8 and TNF.

SUMMARY OF THE INVENTION

This invention relates to the novel compounds of Formula (I) andpharmaceutical compositions comprising a compound of Formula (I) and apharmaceutically acceptable diluent or carrier.

This invention also relates to a method of inhibiting cytokines and thetreatment of a cytokine mediated disease, in a mammal in need thereof,which comprises administering to said mammal an effective amount of acompound of Formula (I).

This invention more specifically relates to a method of inhibiting theproduction of IL-1 in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I).

This invention more specifically relates to a method of inhibiting theproduction of IL-8 in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I).

This invention more specifically relates to a method of inhibiting theproduction of TNF in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I).

Accordingly, the present invention provides a compound of Formula (I):

R₁ is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, quinazolin-4-yl,1-imidazolyl or 1-benzimidazolyl, which heteroaryl ring is optionallysubstituted with one or two substituents each of which is independentlyselected from C₁₋₄ alkyl, halogen, hydroxyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ alkylsulfinyl, CH₂OR₁₂, amino, mono and di- C₁₋₆ alkylsubstituted amino, N(R₁₀)C(O)R_(a) or an N-heterocyclyl ring which ringhas from 5 to 7 members and optionally contains an additional heteroatomselected from oxygen, sulfur or NR₁₅;

R₄ is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which isoptionally substituted by one or two substituents, each of which isindependently selected, and which, for a 4-phenyl, 4-naphth-1-yl,5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro,—C(Z)NR₇R₁₇, —C(Z)OR₁₆, —(CR₁₀R₂₀)_(v)COR₁₂, —SR₅, —SOR₅, —OR₁₂,halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, —ZC(Z)R₁₂, —NR₁₀C(Z)R₁₆, or—(CR₁₀R₂₀)_(v)NR₁₀R₂₀ and which, for other positions of substitution, ishalogen, cyano, —C(Z)NR₁₃R₁₄, —C(Z)OR₃, —(CR₁₀R₂₀)_(m″)COR₃,—S(O)_(m)R₃, —OR₃, —OR₁₂, halo substituted C₁₋₄ alkyl, C₁₋₄ alkyl,—(CR₁₀R₂₀)_(m″)NR₁₀C(Z)R₃, —NR₁₀S(O)_(m′)R₈, —NR₁₀S(O)_(m′)NR₇R₁₇,—ZC(Z)R₃, —ZC(Z)R₁₂, or —(CR₁₀R₂₀)_(m″)NR₁₃R₁₄;

v is 0, or an integer having a value of 1 or 2;

m is 0, or the integer 1 or 2;

m′ is an integer having a value of 1 or 2,

m″ is 0, or an integer having a value of 1 to 5;

R₂ is C₁₋₁₀ alkyl N₃, —(CR₁₀R₂₀)_(n′)OR₉, heterocyclyl, heterocyclylC₁₋₁₀ alkyl, C₁₋₁₀alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇cycloalkenyl, C₅₋₇cycloalkenylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl,heteroaryl, heteroarylC₁₋₁₀alkyl, (CR₁₀R₂₀)_(n)OR₁₁,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)NO₂, (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n′)SO₂R₁₈,(CR₁₀R₂₀)_(n)S(O)_(m′)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₁₁,(CR₁₀R₂₀)_(n)OC(Z)R₁₁, (CR₁₀R₂₀)_(n)C(Z)OR₁₁, (CR₁₀R₂₀)_(n)C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)C(Z)NR₁₁OR₉, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₁₁,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)N(OR₆)C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)N(OR₆)C(Z)R₁₁, (CR₁₀R₂₀)_(n)C(═NOR₆)R₁₁,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₉)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₁₀,5-(R₁₈)-1,2,4-oxadizaol-3-yl or4-(R₁₂)-5-(R₁₈R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl,arylalkyl, heteroaryl, heteroaryl alkyl, cyclcoalkyl, cycloalkyl alkyl,heterocyclic and heterocyclic alkyl groups may be optionallysubstituted;

n is an integer having a value of 1 to 10;

n′ is 0, or an integer having a value of 1 to 10;

Z is oxygen or sulfur;

Ra is hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄alkyl, heterocyclyl, or heterocyclylC₁₋₄alkyl;

R₃ is heterocyclyl, heterocyclylC₁₋₁₀ alkyl or R₈;

R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR₇R₁₇,excluding the moieties —SR₅ being —SNR₇R₁₇ and —S(O)R₅ being —SOH;

R₆ is hydrogen, a pharmaceutically acceptable cation, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroaryl₁₋₁₀alkyl,heterocyclyl, aroyl, or C₁₋₁₀ alkanoyl;

R₇ and R₁₇ is each independently selected from hydrogen or C₁₋₄ alkyl orR₇ and R₁₇ together with the nitrogen to which they are attached form aheterocyclic ring of 5 to 7 members which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR₁₅;

R₈ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₁₀ alkyl,heteroaryl, heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄;wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may beoptionally substituted;

R₉ is hydrogen, —C(Z)R₁₁, optionally substituted C₁₋₁₀ alkyl, S(O)₂R₁₈,optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl;

R₁₀ and R₂₀ is each independently selected from hydrogen or C₁₋₄ alkyl;

R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl;

R₁₂ is hydrogen or R₁₆;

R₁₃ and R₁₄ is each independently selected from hydrogen or optionallysubstituted C₁₋₄ alkyl, optionally substituted aryl or optionallysubstituted aryl-C₁₋₄ alkyl, or together with the nitrogen which theyare attached form a heterocyclic ring of 5 to 7 members which ringoptionally contains an additional heteroatom selected from oxygen,sulfur or NR₉;

R₁₅ is R₁₀ or C(Z)—C₁₋₄ alkyl;

R₁₆ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₇ cycloalkyl;

R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl, aryl₁₋₁₀alkyl,heterocyclyl, heterocyclyl-C₁₋₁₀alkyl, heteroaryl orheteroaryl₁₋₁₀alkyl;

R₁₉ is hydrogen, cyano, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or aryl; or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of Formula (I) may also be used in association withthe veterinary treatment of mammals, other than humans, in need ofinhibition of cytokine inhibition or production. In particular, cytokinemediated diseases for treatment, therapeutically or prophylactically, inanimals include disease states such as those noted herein in the Methodsof Treatment section, but in particular viral infections. Examples ofsuch viruses include, but are not limited to, lentivirus infections suchas, equine infectious anaemia virus, caprine arthritis virus, visnavirus, or maedi virus or retrovirus infections, such as but not limitedto feline immunodeficiency virus (FIV), bovine immunodeficiency virus,or canine immunodeficiency virus or other retroviral infections.

In Formula (I), suitable R₁ moieties includes 4-pyridyl, 4-pyrimidinyl,4-quinolyl, 6-isoquinolinyl, 4-quinazolinyl, 1-imidazolyl and1-benzimidazolyl, of which the 4-pyridyl, 4-pyrimidinyl and 4-quinolylare preferred. More preferred is an optionally substituted 4-pyrimidinylor optionally substituted 4-pyridyl moiety, and most preferred is anoptionally substituted 4-pyrimidinyl ring.

Suitable substituents for the R₁ heteroaryl rings are C₁₋₄ alkyl, halo,OH, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, CH₂OR₁₂, amino,mono- and di-C₁₋₆ alkylsubstituted amino, N(R₁₀)C(O)R_(a) or anN-heterocyclyl ring which ring has from 5 to 7 members and optionallycontains an additional heteroatom selected from oxygen, sulfur or NR₁₅.A preferred substituent for all the R₁ moieties is C₁₋₄ alkyl, inparticular methyl, amino, and mono- and di-C₁₋₆ alkylsubstituted amino,preferably where the amino group is mono-substituted, more preferablywith methyl. The alkyl group in the mono- and di-C₁₋₆ alkylsubstitutedamino moiety may be halo substituted, such as in trifluoro- i.e.,trifluoromethyl or trifluroethyl.

When the R₁ optional substituent is N(R₁₀)C(O) R_(a), wherein R_(a) ishydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl,heteroarylC₁₋₄alkyl, heterocyclyl, or heterocyclylC₁₋₄alkyl C₁₋₄ alkyl,R_(a) is preferably C₁₋₆ alkyl; preferably R₁₀ is hydrogen. It is alsorecognized that the R_(a) moieties, in particular the C₁₋₆ alkyl groupmay be optionally substituted, preferably from one to three times,preferably with halogen, such as fluorine, as in trifluoromethyl ortrifluroethyl.

Preferably, the preferred substituent for R₁ is the amino or mono C₁₋₆alkyl substituted moiety. A preferred ring placement of the R₁substituent on the 4-pyridyl derivative is the 2-position, such as2-methyl-4-pyridyl. A preferred ring placement on the 4-pyrimidinyl ringis also at the 2-position, such as in 2-methyl-pyrimidinyl, 2-aminopyrimidinyl or 2-methylaminopyrimidinyl.

Suitably, R₄ is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl,which is optionally substituted by one or two substituents. Morepreferably R₄ is a phenyl or naphthyl ring. Suitable substitutions forR₄ when this is a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or6-naphth-2-yl moiety are one or two substituents each of which areindependently selected from halogen, —SR₅, —SOR₅, —OR₁₂, CF₃, or—(CR₁₀R₂₀)_(v)NR₁₀R₂₀, and for other positions of substitution on theserings preferred substitution is halogen, —S(O)_(m)R₃, —OR₃, CF₃,—(CR₁₀R₂₀)_(m″)NR₁₃R₁₄, —NR₁₀C(Z)R₃ and —NR₁₀S(O)_(m′)R₈. Preferredsubstituents for the 4-position in phenyl and naphth-1-yl and on the5-position in naphth-2-yl include halogen, especially fluoro and chloroand —SR₅ and —SOR₅ wherein R₅ is preferably a C₁₋₂ alkyl, morepreferably methyl; of which the fluoro and chloro is more preferred, andmost especially preferred is fluoro. Preferred substituents for the3-position in phenyl and naphth-1-yl rings include: halogen, especiallyfluoro and chloro; —OR₃, especially C₁₋₄ alkoxy; CF₃, NR₁₀R₂₀, such asamino; —NR₁₀C(Z)R₃, especially —NHCO(C₁₋₁₀ alkyl); —NR₁₀S(O)_(m′)R₈,especially —NHSO₂(C₁₋₁₀ alkyl), and —SR₃ and —SOR₃ wherein R₃ ispreferably a C₁₋₂ alkyl, more preferably methyl. When the phenyl ring isdisubstituted preferably it is two independent halogen moieties, such asfluoro and chloro, preferably di-chloro and more preferably in the3,4-position. It is also preferred that for the 3-position of both the—OR₃ and —ZC(Z)R₃ moietites, R₃ may also include hydrogen.

Preferably, the R₄ moiety is an unsubstituted or substituted phenylmoiety. More preferably, R₄ is phenyl or phenyl substituted at the4-position with fluoro and/or substituted at the 3-position with fluoro,chloro, C₁₋₄ alkoxy, methane-sulfonamido or acetamido, or R₄ is a phenyldi-substituted at the 3,4-position independently with chloro or fluoro,more preferably chloro. Most preferably, R₄ is a 4-fluorophenyl.

In Formula (I), Z is oxygen or sulfur, preferably oxygen.

Suitably, R₂ is C₁₋₁₀ alkyl N₃, —(CR₁₀R₂₀)_(n′)OR₉, heterocyclyl,heterocyclylC₁₋₁₀ alkyl, C₁₋₁₀alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenyl C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl,heteroaryl, heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)NO₂, (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n′)SO₂R₁₈,(CR₁₀R₂₀)_(n)S(O)_(m′)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₁₁,(CR₁₀R₂₀)_(n)OC(Z)R₁₁, (CR₁₀R₂₀)_(n)C(Z)OR₁₁, (CR₁₀R₂₀)_(n)C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)C(Z)NR₁₁OR₉, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₁₁,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)N(OR₆)C(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)N(OR₆)C(Z)R₁₁, (CR₁₀R₂₀)_(n)C(═NOR₆)R₁₁,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₉)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₁₃R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₁₀,5-(R₁₈)-1,2,4-oxadizaol-3-yl or4-(R₁₂)-5-(R₁₈R₁₉)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein thecycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclic, and heterocyclic alkyl moieties may beoptionally substituted; wherein n is an integer having a value of 1 to10, m is 0, or the integer 1 or 2; n′ is 0, or an integer having a valueof 1 to 10; and m′ is 1 or 2. Preferably n is 1 to 4.

Preferably R₂ is an optionally substituted heterocyclyl ring, andoptionally substituted heterocyclylC₁₋₁₀ alkyl, an optionallysubstituted C₁₋₁₀ alkyl, an optionally substituted C₃₋₇cycloalkyl, anoptionally substituted C₃₋₇cycloalkyl C₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)C(Z)OR₁₁group, (CR₁₀R₂₀)_(n)NR₁₃R₁₄, (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, an optionally substituted aryl; an optionallysubstituted arylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁, (CR₁₀R₂₀)_(n)C(Z)R₁₁, or(CR₁₀R₂₀)_(n)C(═NOR₆)R₁₁ group.

More preferably R₂ is an optionally substituted heterocyclyl ring, andoptionally substituted heterocyclylC₁₋₁₀ alkyl, optionally substitutedaryl, (CR₁₀R₂₀)_(n)NR₁₃R₁₄, or (CR₁₀R₂₀)_(n)C(Z)OR₁₁ group.

When R₂ is an optionally substituted heterocyclyl the ring is preferablya morpholino, pyrrolidinyl, or a piperidinyl group. When the ring isoptionally substituted the substituents may be directly attached to thefree nitrogen, such as in the piperidinyl group or pyrrole ring, or onthe ring itself. Preferably the ring is a piperidine or pyrrole, morepreferably piperidine. The heterocyclyl ring may be optionallysubstituted one to four times independently by halogen; C₁₋₄ alkyl;aryl, such as phenyl; aryl alkyl, such as benzyl—wherein the aryl oraryl alkyl moieties themselves may be optionally substituted (as in thedefinition section below); C(O)OR₁₁, such as the C(O)C₁₋₄ alkyl orC(O)OH moieties; C(O)H; C(O)C₁₋₄ alkyl, hydroxy substituted C₁₋₄ alkyl,C₁₋₄ alkoxy, S(O)_(m)C₁₋₄ alkyl (wherein m is 0, 1, or 2), NR₁₀R₂₀(wherein R₁₀ and R₂₀ are independently hydrogen or C₁₋₄alkyl).

Preferably if the ring is a piperidine, the ring is attached to theimidazole at the 4-position, and the substituents are directly on theavailable nitrogen, i.e. a 1-Formyl-4-piperidine, 1-benzyl-4-piperidine,1-methyl-4-piperidine, 1-ethoxycarbonyl-4-piperidine. If the ring issubstituted by an alkyl group and the ring is attached in the4-position, it is preferably substituted in the 2 or 6 position or both,such as 2,2,6,6-tetramethyl-4-piperidine. Similarly, if the ring is apyrrole, the ring is attached to the imidazole at the 3-position, andthe substituents are all directly on the available nitrogen.

When R₂ is an optionally substituted heterocyclyl C₁₋₁₀ alkyl group, thering is preferably a morpholino, pyrrolidinyl, or a piperidinyl group.Preferably this alkyl moiety is from 1 to 4, more preferably 3 or 4, andmost preferably 3, such as in a propyl group. Preferred heterocyclicalkyl groups include but are not limited to, morpholino ethyl,morpholino propyl, pyrrolidinyl propyl, and piperidinyl propyl moieties.The heterocyclic ring herein is also optionally substituted in a similarmanner to that indicated above for the direct attachment of theheterocyclyl.

When R₂ is an optionally substituted C₃₋₇cycloalkyl, or an optionallysubstituted C₃₋₇cycloalkyl C₁₋₁₀ alkyl, the cycloalkyl group ispreferably a C₅ to C₆ ring which ring may be optionally substituted 1 ormore times independently by halogen, such as fluorine, chlorine, bromineor iodine; hydroxy; C₁₋₁₀ alkoxy, such as methoxy or ethoxy; S(O)_(m)alkyl, wherein m is 0, 1, or 2, such as methyl thio, methylsulfinyl ormethyl sulfonyl; amino, mono & di-substituted amino, such as in theNR₇R₁₇ group; or where the R₇R₁₇ may cyclize together with the nitrogento which they are attached to form a 5 to 7 membered ring whichoptionally includes an additional heteroatom selected from O/N/S; C₁₋₁₀alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl;halosubstituted alkyl, such as CF₃; hydroxy substituted C₁₋₁₀alkyl;C(O)OR₁₁, such as the free acid or methyl ester derivative; anoptionally substituted aryl, such as phenyl; an optionally substitutedarylalkyl, such as benzyl of phenethyl; and further where these arylmoieties may also be substituted one to two times by halogen; hydroxy;C₁₋₁₀ alkoxy; S(O)_(m) alkyl; amino, mono & di-substituted amino, suchas in the NR₇R₁₇ group; alkyl or halosubstituted alkyl.

When R₂ is (CR₁₀R₂₀)_(n)NR₁₃R₁₄, R₁₃ and R₁₄ are as defined in Formula(I), that is R₁₃ and R₁₄ are each independently selected from hydrogen,optionally substituted C₁₋₄ alkyl, optionally substituted aryl or anoptionally substituted aryl-C₁₋₄ alkyl, or together with the nitrogenwhich they are attached form a heterocyclic ring of 5 to 7 members whichring optionally contains an additional heteroatom selected from oxygen,sulfur or NR₉. It is recognized that in some instances this can yieldthe same moiety as a heterocyclic C₁₋₁₀ alkyl moiety noted above whichis also a suitable R₂ variable. Preferably R₁₃ and R₁₄ are independentlyhydrogen, C₁₋₄ alkyl, preferably methyl, or benzyl. The n term ispreferably 1 to 4, more preferably 3 or 4, and most preferably 3, suchas in a propyl group. Preferred groups include, but are not limited to,aminopropyl, (N-methyl-N-benzyl)aminopropyl,(N-Phenylmethyl)amino-1-propyl, or diethylamino propyl.

When R₂ is a (CR₁₀R₂₀)_(n)C(Z)OR₁₁ group, R₁₁ is suitably hydrogen, C₁₋₄alkyl, especially methyl. The n term is preferably 1 to 4, morepreferably 2 or 3, such as in an ethyl or propyl group. Preferred groupsinclude, but are not limited to, carboxymethyl-1-butyl,carboxy-1-propyl, or 2-acetoxyethyl.

When R₂ is a (CR₁₀R₂₀)_(n)S(O)_(m)R₁₈ group m is 0, 1, or 2, and R₁₈ ispreferably aryl, especially phenyl, or C₁₋₁₀ alkyl, especially methyl.The n term is preferably 1 to 4, more preferably 2 or 3, such as in anethyl or propyl group.

When R₂ is a (CR₁₀R₂₀)_(n)OR₁₁ group, R₁₁ is suitably hydrogen, aryl,especially phenyl, or C₁₋₁₀ alkyl, especially methyl or ethyl. The nterm is preferably 1 to 4, more preferably 2 or 3, such as in an ethylor propyl group.

When R₂ is a (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈ group, R₁₈ is suitably alkyl,especially methyl. The n term is preferably 1 to 4, more preferably 2 or3, such as in an ethyl or propyl group.

When R₂ is a optionally substituted aryl, the aryl is preferably phenyl.The aryl ring may be optionally substituted one or more times,preferably by one or two substituents, independently selected from C₁₋₄alkyl, halogen, especially fluoro or chloro, (CR₁₀R₂₀)_(t)OR₁₁,—(CR₁₀R₂₀)_(t)NR₁₀R₂O, especially amino or mono- or di-alkylamino—(CR₁₀R₂₀)_(t)S(O)_(m)R₁₈, wherein m is 0, 1 or 2; —SH—,—(CR₁₀R₂₀)_(n)NR₁₃R₁₄, —NR₁₀C(Z)R₃ (such —NHCO(C₁₋₁₀ alkyl));—NR₁₀S(O)_(m)R₈ (such as —NHSO₂(C₁₋₁₀ alkyl)); and t is 0, or an integerof 1 to 4. Preferably the phenyl is substituted in the 3 or 4- positionby —(CR₁₀R₂₀)_(t)S(O)_(m)R₁₈, and R₁₈ is preferably C₁₋₁₀ alkyl,especially methyl.

When R₂ is an optionally substituted heteroaryl or heteroarylalkyl groupthe ring may be optionally substituted one or more times, preferably byone or two substituents, independently selected from one or more times,by C₁₋₄ alkyl, halogen, especially fluoro or chloro, (CR₁₀R₂₀)_(t)OR₁₁,—(CR₁₀R₂₀)_(t)NR₁₀R₂₀, especially amino or mono- or di-alkylamino—(CR₁₀R₂₀)_(t)S(O)_(m)R₁₈, wherein m is 0, 1 or 2; —SH—,—(CR₁₀R₂₀)_(n)—NR₁₃R₁₄, —NR₁₀C(Z)R₃ (such —NHCO(C₁₋₁₀ alkyl));—NR₁₀S(O)_(m)R₈ (such as —NHSO₂(C₁₋₁₀ alkyl)); t is 0, or an integer of1 to 4.

One skilled in the art would readily recognize that when R₂ is a(CR₁₀R₂₀)_(n)OC(Z)R₁₁, or (CR₁₀R₂₀)_(n)OC(Z)NR₁₃R₁₄ moiety, or anysimilarly substituted group that n is preferably at least 2 which willallow for the synthesis of stable compounds.

Preferably R₂ is a C₁₋₄ alkyl (branched and unbranched), especiallymethyl, methylthio propyl, a methylsulfinyl propyl, an amino propyl,N-methyl-N-benzylamino propyl group, diethylamino propyl, cyclopropylmethyl, morpholinyl butyl, morpholinyl propyl, a morpholinyl ethyl, apiperidine or a substituted piperidine. More preferably R₂ is a methyl,isopropyl, butyl, t-butyl, n-propyl, methylthiopropyl, or methylsulfinylpropyl, morpholino propyl, morpholinyl butyl, phenyl substituted byhalogen, thioalkyl or sulfinyl alkyl such as a methylthio,methylsulfinyl or methylsulfonyl moiety; piperidinyl,1-Formyl-4-piperidine, 1-benzyl-4-piperidine, 1-methyl-4-piperidine, ora 1-ethoxycarbonyl-4-piperidine.

In all instances herein where there is an alkenyl or alkynyl moiety as asubstituent group, the unsaturated linkage, i.e., the vinylene oracetylene linkage is preferably not directly attached to the nitrogen,oxygen or sulfur moieties, for instance in OR₃, or for certain R₂moieties.

As used herein, “optionally substituted” unless specifically definedshall mean such groups as halogen, such as fluorine, chlorine, bromineor iodine; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy, suchas methoxy or ethoxy; S(O)m alkyl, wherein m is 0, 1 or 2, such asmethyl thio, methylsulfinyl or methyl sulfonyl; amino, mono &di-substituted amino, such as in the NR₇R₁₇ group; or where the R₇R₁₇may together with the nitrogen to which they are attached cyclize toform a 5 to 7 membered ring which optionally includes an additionalheteroatom selected from O/N/S; C₁₋₁₀ alkyl, cycloalkyl, or cycloalkylalkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. orcyclopropyl methyl; halosubstituted C₁₋₁₀ alkyl, such CF₃; an optionallysubstituted aryl, such as phenyl, or an optionally substitutedarylalkyl, such as benzyl or phenethyl, wherein these aryl moieties mayalso be substituted one to two times by halogen; hydroxy; hydroxysubstituted alkyl; C₁₋₁₀ alkoxy; S(O)_(m) alkyl; amino, mono &di-substituted amino, such as in the NR₇R₁₇ group; alkyl, or CF₃.

In a preferred subgenus of compounds of Formula (I), R₁ is 4-pyridyl,2-alkyl-4-pyridyl, 4-quinolyl, 4-pyrimidinyl, 2-amino-4-pyrimidinyl or2-methylamino-4-pyrimidinyl; R₂ is morpholinyl propyl, aminopropyl,piperidinyl, N-benzyl-4-piperidinyl, or N-methyl-4-piperidinyl; and R₄is phenyl or phenyl substituted one or two times by fluoro, chloro, C₁₋₄alkoxy, —S(O)_(m) alkyl, methanesulfonamido or acetamido.

A preferred subgrouping of compounds of Formula (I) are those where R₂is other than methyl when R₁ is pyridyl, and R₄ is an optionallysubstituted phenyl.

Suitable pharmaceutically acceptable salts are well known to thoseskilled in the art and include basic salts of inorganic and organicacids, such as hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methane sulphonic acid, ethane sulphonic acid, aceticacid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,phenylacetic acid and mandelic acid. In addition, pharmaceuticallyacceptable salts of compounds of Formula (I) may also be formed with apharmaceutically acceptable cation, for instance, if a substituent groupcomprises a carboxy moiety. Suitable pharmaceutically acceptable cationsare well known to those skilled in the art and include alkaline,alkaline earth, ammonium and quaternary ammonium cations.

The following terms, as used herein, refer to:

“halo” or “halogens”, include the halogens: chloro, fluoro, bromo andiodo.

“C₁₋₁₀ alkyl” or “alkyl”—both straight and branched chain radicals of 1to 10 carbon atoms, unless the chain length is otherwise limited,including, but not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.

The term “cycloalkyl” is used herein to mean cyclic radicals, preferablyof 3 to 8 carbons, including but not limited to cyclopropyl,cyclopentyl, cyclohexyl, and the like.

The term “cycloalkenyl” is used herein to mean cyclic radicals,preferably of 5 to 8 carbons, which have at least one bond including butnot limited to cyclopentenyl, cyclohexenyl, and the like.

The term “alkenyl” is used herein at all occurrences to mean straight orbranched chain radical of 2-10 carbon atoms, unless the chain length islimited thereto, including, but not limited to ethenyl, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

“aryl”—phenyl and naphthyl;

“heteroaryl” (on its own or in any combination, such as “heteroaryloxy”,or “heteroaryl alkyl”)—a 5-10 membered aromatic ring system in which oneor more rings contain one or more heteroatoms selected from the groupconsisting of N, O or S, such as, but not limited, to pyrrole, pyrazole,furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine,pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, orbenzimidazole.

“heterocyclic” (on its own or in any combination, such as“heterocyclylalkyl”)—a saturated or partially unsaturated 4-10 memberedring system in which one or more rings contain one or more heteroatomsselected from the group consisting of N, O, or S; such as, but notlimited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.

The term “aralkyl” or “heteroarylalkyl” or “heterocyclicalkyl” is usedherein to mean C₁₋₄ alkyl as defined above attached to an aryl,heteroaryl or heterocyclic moiety as also defined herein unlessotherwise indicate.

“sulfinyl”—the oxide S (O) of the corresponding sulfide, the term “thio”refers to the sulfide, and the term “sulfonyl” refers to the fullyoxidized S (O)₂ moiety.

“aroyl”—a C(O)Ar, wherein Ar is as phenyl, naphthyl, or aryl alkylderivative such as defined above, such group include but are not limitedto benzyl and phenethyl.

“alkanoyl”—a C(O)C₁₋₁₀ alkyl wherein the alkyl is as defined above.

For the purposes herein the “core” 4-pyrimidinyl moiety for R₁ or R₂ is

referred to as the formula:

The compounds of the present invention may contain one or moreasymmetric carbon atoms and may exist in racemic and optically activeforms. All of these compounds are included within the scope of thepresent invention.

Exemplified compounds of Formula (I) include:

1-[3-(4-Morpholinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-(3-Chloropropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-(3-Azidopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-(3-Aminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-(3-Methylsulfonamidopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-[3-(N-Phenylmethyl)aminopropyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-[3-(N-Phenylmethyl-N-methyl)aminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-[3-(1-Pyrrolidinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-(3-Diethylaminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-[3-(1-Piperidinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-[3-(Methylthio)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-[2-(4-Morpholinyl)ethyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-[3-(4-Morpholinyl)propyl]-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole;

(+/−)-1-[3-(4-Morpholinyl)propyl]-4-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole;

1-[3-(N-methyl-N-benzyl)aminopropyl]-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole;

1-[3-(N-methyl-N-benzyl)aminopropyl]-4-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole;

1-[4-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-[4-(Methylsulfinyl)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-[3-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

(+/−)-1-[3-(Methylsulfinyl)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-[2-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-[2-(Methylsulfinyl)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-[4-(4-Morpholinyl)butyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-Cyclopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-Isopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-Cyclopropylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-tert-Butyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-(2,2-Diethoxyethyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-Formylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-Hydroxyiminylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-Cyanomethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-[3-(4-Morpholinyl)propyl)-4-(4-fluorophenyl)-5-(2-methylpyrid-4-yl)imidazole;

4-(4-Fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(2-chloropyridin-4-yl)imidazole;

4-(4-Fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(2-amino-4-pyridinyl)imidazole;

1-(4-Carboxymethyl)propyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-(4-Carboxypropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-(3-Carboxymethyl)ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-(3-Carboxy)ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

1-(1-Benzylpiperidin-4-yl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole;

5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-[3-(4-Morpholinyl)propyl]imidazole;

5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(1-benzylpiperidin-4-yl)imidazole;

5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(2-propyl)imidazole;

5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(cyclopropylmethyl)imidazole;

5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(1-carboxyethyl-4-piperidinyl)imidazole;

5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;

1-Methyl-4-phenyl-5-(4-pyridyl)imidazole;

1-Methyl-4-[3-(chlorophenyl)]-5-[4-pyridinyl]imidazole;

1-Methyl-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole;

(+/−)-1-Methyl-4-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole;

(+/−)-4-(4-Fluorophenyl)-1-[3-(methylsulfinyl)propyl]-5-(4-pyridinyl)imidazole;

4-(4-Fluorophenyl)-1-[(3-methylsulfonyl)propyl]-5-(4-pyridinyl)imidazole;

1-(3-Phenoxypropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

1-[3-(Phenylthio)propyl]-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

1-[3-(4-Morpholinyl)propyl]-4-(4-fluorophenyl)-5-(4-quinolyl)imidazole;

(+/−)-1-(3-Phenylsulfinylpropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

1-(3-Ethoxypropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

1-(3-Phenylsulfonylpropyl-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

1-[3-(4-Morpholinyl)propyl]-4-(3-chlorophenyl)-5-(4-pyridyl)imidazole;

1-[3-(4-Morpholinyl)propyl]-4-(3,4-dichlorophenyl)-5-(4-pyridyl)imidazole;

4-[4-(4-Fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(pyrimid-2-one-4-yl)imidazole;

4-(4-Fluorophenyl)-5-[2-(methylthio)-4-pyrimidinyl]-1-[3-(4-morpholinyl)propyl]imidazole;

(+/−)-4-(4-Fluorophenyl)-5-[2-(methylsulfinyl)-4-pyrimidinyl]-1-[3-(4-morpholinyl)propyl]imidazole;

(E)-1-(1-Propenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

1-(2-Propenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

5-[(2-N,N-Dimethylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-[3-(4-morpholinyl)propyl]imidazole;

1-[3-(4-Morpholinyl)propyl]-5-(4-pyridinyl)-4-[4-(trifluoromethyl)phenyl]imidazole;

1-[3-(4-Morpholinyl)propyl]-5-(4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]imidazole;

1-(Cyclopropylmethyl)-4-(3,4-dichlorophenyl)-5-(4-pyridinyl)imidazole;

1-(Cyclopropylmethyl)-4-(3-trifluoromethylphenyl)-5-(4-pyridinyl)imidazole;

1-(Cyclopropylmethyl)-4-(4-fluorophenyl)-5-(2-methylpyrid-4-yl)imidazole;

1-[3-(4-Morpholinyl)propyl]-5-(4-pyridinyl)-4-(3,5-bistrifluoromethylphenyl)-imidazole;

5-[4-(2-Aminopyrimidinyl)]-4-(4-fluorophenyl)-1-(2-carboxy-2,2-dimethylethyl)imidazole;

1-(-Formyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole;

5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(1-methyl-4-piperidinyl)imidazole;

1-(2,2-Dimethyl-3-morpholin-4-yl)propyl-4-(4-fluorophenyl)-5-(2-Amino-4-pyrimidinyl)imidazole;

4-(4-Fluorophenyl)-5-(4-pyridyl)-1-(2-acetoxyethyl)imidazole;

5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(1-benzylpyrrolin-3-yl)imidazole;

5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(2,2,6,6-tetramethylpiperidin-4-yl)imidazole;

5-[4-(2-N-Methylamino)pyrimidinyl}-4-(4-fluorophenyl)-1-(4-N-methylpiperidine)imidazole;

5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-N-morpholino-1-propyl)imidazole;

5-[4-(2-N-Methylamino)pyrimidinyl}-4-(4-fluorophenyl)-1-(4-piperidine)imidazole;

5-[(2-Ethylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazole;

4-(4-Fluorophenyl)-5-[2-(isopropyl)aminopyrimidiny-4-yl]-1-(1-methylpiperdin-4-yl)imidazole;

5-(2-Acetamido-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-N-morpholino-1-propyl)imidazole;

5-(2-Acetamido-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(1-methyl-4-piperidinyl)imidazole;

5-[4-(2-N-Methylthio)pyrimidinyl}-4-(4-fluorophenyl)-1-(4-piperidine)imidazole

4-(Fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methylthio-4-pyrimidinyl)imidazole

4-(Fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methysulfinyl-4-pyrimidinyl)imidazole

1-tert-Butyl-4-(4-fluorophenyl)-5-(2-methysulfinyl-4-pyrimidinyl)imidazole;

5-[4-(2-Aminopyrimidinyl)]-4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidinyl)imidazole

5-[4-(2-N-Methylamino-4-pyrimidinyl)]-4-(4-fluorophenyl)-1-(2,2,6,6-tetra-methyl-4-piperidine)imidazole

5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-thiopyranyl)imidazole

5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-pyranyl)imidazole

5-(2-Methylamino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(2-cyanoethyl)imidazole

5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-sulfinylpyranyl)imidazole

5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-sulfonylpyranyl)imidazole

5-(2-Methylamino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl-4-piperidinyl)imidazole

5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(trifluoroacetyl-4-piperidinyl)imidazole

5-(4-Pyridyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;

5-(4-Pyridyl)-4-(4-fluorophenyl)-1-(1-t-butoxycarbonyl-4-piperidinyl)imidazole.

Preferred compounds of Formula (I) include:

5-[4-(2-Amino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-N-morpholino-1-propyl)imidazole;

5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-N-morpholino-1-propyl)imidazole;

5-[4-(2-Aminopyrimidinyl)-4-(4-fluorophenyl)-1-(1-benzyl-4-piperidinyl)imidazole;

5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole;

5-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-N-methylpiperidinyl)imidazole;

5-[4-(2-N-Methylamino)pyrimidinyl}-4-(4-fluorophenyl)-1-(4-N-methylpiperidinyl)imidazole;

5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(2,2,6,6-tetramethylpiperidin-4-yl)imidazole;

5-[4-(2-N-Methylamino)pyrimidinyl}-4-(4-fluorophenyl)-1-(4-piperidine)imidazole;

Another aspect of the present invention is the compound,4-phenyl-5-[4-pyridyl)imidazole. Another aspect of the present inventionis a pharmaceutical composition comprising a carrier or diluent andeffective amount of 4-phenyl-5-[4-pyridyl)imidazole. Yet another aspectof the present invention is the novel method of treating a cytokinemediated disease state, in a mammal in need thereof, with an effectiveamount of 4-phenyl-5-[4-pyridyl)imidazole.

For purposes herein the dosage ranges, formulation details, and methodsof making are analogous to the compounds of Formula (I).

In a further aspect the present invention provides for compounds of theFormula (II) having the structure:

wherein p is 0, or 2; R₄ is as defined for Formula (I) and Ar is anoptionally substituted aryl as defined herein. Suitably, Ar is phenyloptionally substituted by C₁₋₄alkyl, C₁₋₄ alkoxy or halo. Preferably Aris phenyl or 4-methylphenyl, i.e. a tosyl derivative. Compounds ofFormula (II) are believed novel, provided than when Ar is tosyl, and pis 0 or 2, then R₄ is not an unsubstituted phenyl.

The compounds of Formula (I) may be obtained by applying syntheticprocedures, some of which are illustrated in Schemes I to XI herein. Thesynthesis provided for in these Schemes is applicable for the producingcompounds of Formula (I) having a variety of different R₁, R₂, and R₄groups which are reacted, employing optional substituents which aresuitably protected, to achieve compatibility with the reactions outlinedherein. Subsequent deprotection, in those cases, then affords compoundsof the nature generally disclosed. Once the imidazole nucleus has beenestablished, further compounds of Formula (I) may be prepared byapplying standard techniques for functional group interconversion, wellknown in the art.

For instance: —C(O)NR₁₃R₁₄ from —CO₂CH₃ by heating with or withoutcatalytic metal cyanide, e.g. NaCN, and HNR₁₃R₁₄ in CH₃H; —OC(O)R₃ from—OH with e.g., ClC(O)R₃ in pyridine; —NR₁₀—C(S)NR₁₃R₁₄ from —NHR₁₀ withan alkylisothiocyante or thiocyanic acid; NR₆C(O)OR₆ from —NHR₆ with thealkyl chloroformate; —NR₁₀C(O)NR₁₃R₁₄ from —NHR₁₀ by treatment with anisocyanate, e.g. HN═C═O or R₁₀N═C═O; —NR₁₀—C(O)R₈ from —NHR₁₀ bytreatment with Cl—C(O)R₃ in pyridine; —C(═NR₁₀)NR₁₃R₁₄ from—C(NR₁₃R₁₄)SR₃ with H₃NR₃ ⁺OAc⁻ by heating in alcohol; —C(NR₁₃R₁₄)SR₃from —C(S)NR₁₃R₁₄ with R₆-I in an inert solvent, e.g. acetone;—C(S)NR₁₃R₁₄ (where R₁₃ or R₁₄ is not hydrogen) from —C(S)NH₂ withHNR₁₃R₁₄—C(═NCN)—NR₁₃R₁₄ from —C(═NR₁₃R₁₄)—SR₃ with NH₂CN by heating inanhydrous alcohol, alternatively from —C(═NH)—NR₁₃R₁₄ by treatment withBrCN and NaOEt in EtOH; —NR₁₀—C(═NCN)SR₈ from —NHR₁₀ by treatment with(R₈S)₂C═NCN; —NR₁₀SO₂R₃ from —NHR₁₀ by treatment with ClSO₂R₃ by heatingin pyridine; —NR₁₀C(S)R₃ from —NR₁₀C(O)R₈ by treatment with Lawesson'sreagent[2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide];—NR₁₀SO₂CF₃ from —NHR₆ with triflic anhydride and base wherein R₃, R₆,R₁₀, R₁₃ and R₁₄ are as defined in Formula (I) herein.

Precursors of the groups R₁, R₂ and R₄ can be other R₁, R₂ and R₄ groupswhich can be interconverted by applying standard techniques forfunctional group interconversion. For example a compound of the formula(I) wherein R₂ is halo-substituted C₁₋₁₀ alkyl can be converted to thecorresponding C₁₋₁₀ alkylN₃ derivative by reacting with a suitable azidesalt, and thereafter if desired can be reduced to the correspondingC₁₋₁₀alkylNH₂ compound, which in turn can be reacted with R₁₈S(O)₂Xwherein X is halo (e.g., chloro) to yield the correspondingC₁₋₁₀alkylNHS(O)₂R₁₈ compound.

Alternatively a compound of the formula (I) where R₂ is halo-substitutedC₁₋₁₀-alkyl can be reacted with an amine R₁₃R₁₄NH to yield thecorresponding C₁₋₁₀-alkylNR₁₃R₁4 compound, or can be reacted with analkali metal salt of R₁₈SH to yield the corresponding C₁₋₁₀alkylSR₁₈compound.

Referring to Scheme I the compounds of Formula (I) are suitably preparedby reacting a compound of the Formula (II) with a compound of theFormula (III) wherein p is 0 or 2, R₁, R₂ and R₄ are as defined herein,for Formula (I), or are precursors of the groups R₁, R₂ and R₄, and Aris an optionally substituted phenyl group, and thereafter if necessaryconverting a precursor of R₁, R₂ and R₄ to a group R₁, R₂ and R₄.

Suitably, the reaction is performed at ambient temperature or withcooling (e.g. −50° to 10°) or heating in an inert solvent such asmethylene chloride, DMF, tetrahydrofuran, toluene, acetonitrile, ordimethoxyethane in the presence of an appropriate base such as1,8-diazabicyclo [5.4.0.] undec-7-ene (DBU) or a guaridine base such as1,5,7-triaza-bicyclo [4.4.0] dec-5-ene (TBD). The intermediates offormula (II) have been found to be very stable and capable of storagefor a long time. Preferably, p is 2.

Reaction a compound of the Formula (II) wherein p=2, with a compound ofthe Formula (III)—Scheme I gives consistently higher yields of compoundsof Formula (I) than when p=0. In addition, the reaction of Formula (II)compounds wherein p=2 is more environmentally and economicallyattractive. When p=0, the preferred solvent used is methylene chloride,which is environmentally unattractive for large scale processing, andthe preferred base, TBD, is also expensive, and produces some byproductsand impurities, than when using the commercially attractive synthesis(p=2) as further described herein.

As noted, Scheme I utilizes the 1,3-dipolar cycloadditions of an anionof a substituted aryl thiomethylisocyanide (when p=0) to an imine. Morespecifically, this reaction requires a strong base, such as an aminebase, to be used for the deprotonation step. The commercially availableTBD is preferred although t-butoxide, Li+ or Na+, or K+hexamethyldisilazide may also be used. While methylene chloride is theprefered solvent, other halogenated solvents, such as chloroform orcarbon tetrachloride; ethers, such as THF, DME, DMF, diethylether,t-butyl methyl ether; as well as acetonitrile, toluene or mixturesthereof can be utiltized. The reaction may take place from about −20° C.to about; 40° C., preferably from about 0° C. to about 23° C., morepreferably from about 0° C. to about 10° C., and most preferably about4° C. for reactions involving an R₁ group of pyrimidine. For compoundswherein R₁ is pyridine, it is recognized that varying the reactionsconditions of both temperature and solvent may be necessary, such asdecreasing temperatures to about −50° C. or changing the solvent to THF.

In a further process, compounds of Formula (I) may be prepared bycoupling a suitable derivative of a compound of Formula (IX):

wherein T₁ is hydrogen and T₄ is R₄, or alternatively T₁ is R₁ and T₄ isH in which R₁, R₂ and R₄ are as hereinbefore defined; with: (i) when T₁is hydrogen, a suitable derivative of the heteroaryl ring R₁H, underring coupling conditions, to effect coupling of the heteroaryl ring R₁to the imidazole nucleus at position 5; (ii) when T₄ is hydrogen, asuitable derivative of the aryl ring R₄H, under ring couplingconditions, to effect coupling of the aryl ring R₄ to the imidazolenucleus at position 4.

Such aryl/heteroaryl coupling reactions are well known to those skilledin the art. In general, an organometallic synthetic equivalent of ananion of one component is coupled with a reactive derivative of thesecond component, in the presence of a suitable catalyst. The anionequivalent may be formed from either the imidazole of Formula (IX), inwhich case the aryl/heteroaryl compound provides the reactivederivative, or the aryl/heteroaryl compound in which case the imidazoleprovides the reactive derivative. Accordingly, suitable derivatives ofthe compound of Formula (IX) or the aryl/heteroaryl rings includeorganometallic derivatives such as organomagnesium, organozinc,organostannane and boronic acid derivatives and suitable reactivederivatives include the bromo, iodo, fluorosulfonate andtrifluoromethanesulphonate derivatives. Suitable procedures aredescribed in WO 91/19497, the disclosure of which is incorporated byreference herein.

Suitable organomagnesium and organozinc derivatives of a compound ofFormula (IX) may be reacted with a halogen, fluorosulfonate or triflatederivative of the heteroaryl or aryl ring, in the presence of a ringcoupling catalyst, such as a palladium (O) or palladium (II) catalyst,following the procedure of Kumada et al., Tetrahedron Letters, 22, 5319(1981). Suitable such catalysts includetetrakis-(triphenylphosphine)palladium andPdCl₂[1,4-bis-(diphenylphosphino)-butane], optionally in the presence oflithium chloride and a base, such as triethylamine. In addition, anickel (II) catalyst, such as Ni(II)Cl₂(1,2-biphenylphosphino)ethane,may also be used for coupling an aryl ring, following the procedure ofPridgen et al., J. Org. Chem, 1982, 47, 4319. Suitable reaction solventsinclude hexamethylphosphor-amide. When the heteroaryl ring is 4-pyridyl,suitable derivatives include 4-bromo- and 4-iodo-pyridine and thefluorosulfonate and triflate esters of 4-hydroxy pyridine. Similarly,suitable derivatives for when the aryl ring is phenyl include the bromo,fluorosulfonate, triflate and, preferably, the iodo-derivatives.Suitable organomagnesium and organozinc derivatives may be obtained bytreating a compound of Formula (IX) or the bromo derivative thereof withan alkyllithium compound to yield the corresponding lithium reagent bydeprotonation or transmetallation, respectively. This lithiumintermediate may then be treated with an excess of a magnesium halide orzinc halide to yield the corresponding organometallic reagent.

A trialkyltin derivative of the compound of Formula (IX) may be treatedwith a bromide, fluorosulfonate, triflate, or, preferably, iodidederivative of an aryl or heteroaryl ring compound, in an inert solventsuch as tetrahydrofuran, preferably containing 10%hexamethylphosphoramide, in the presence of a suitable couplingcatalyst, such as a palladium (O) catalyst, for instancetetrakis-(triphenylphosphine)-palladium, by the method described in byStille, J. Amer. Chem. Soc, 1987, 109, 5478, U.S. Pat. Nos. 4,719,218and 5,002,942, or by using a palladium (II) catalyst in the presence oflithium chloride optionally with an added base such as triethylamine, inan inert solvent such as dimethyl formamide. Trialkyltin derivatives maybe conveniently obtained by metallation of the corresponding compound ofFormula (IX) with a lithiating agent, such as s-butyl-lithium orn-butyllithium, in an ethereal solvent, such as tetrahydrofuran, ortreatment of the bromo derivative of the corresponding compound ofFormula (IX) with an alkyl lithium, followed, in each case, by treatmentwith a trialkyltin halide. Alternatively, the bromo- derivative of acompound of Formula (IX) may be treated with a suitable heteroaryl oraryl trialkyl tin compound in the presence of a catalyst such astetrakis-(triphenyl-phosphine)-palladium, under conditions similar tothose described above.

Boronic acid derivatives are also useful. Hence, a suitable derivativeof a compound of Formula (IX), such as the bromo, iodo, triflate orfluorosulphonate derivative, may be reacted with a heteroaryl- oraryl-boronic acid, in the presence of a palladium catalyst such astetrakis-(triphenylphosphine)-palladium orPdCl₂[1,4-bis-(diphenyl-phosphino)-butane] in the presence of a basesuch as sodium bicarbonate, under reflux conditions, in a solvent suchas dimethoxyethane (see Fischer and Haviniga, Rec. Trav. Chim. Pays Bas,84, 439, 1965, Snieckus, V., Tetrahedron Lett., 29, 2135, 1988 andTerashimia, M., Chem. Pharm. Bull., 11, 4755, 1985). Non-aqueousconditions, for instance, a solvent such as DMF, at a temperature ofabout 100° C., in the presence of a Pd(II) catalyst may also be employed(see Thompson W J et al, J Org Chem, 49, 5237, 1984). Suitable boronicacid derivatives may be prepared by treating the magnesium or lithiumderivative with a trialkylborate ester, such as triethyl, tri-iso-propylor tributylborate, according to standard procedures.

In such coupling reactions, it will be readily appreciated that dueregard must be exercised with respect to functional groups present inthe compounds of Formula (IX). Thus, in general, amino and sulfursubstituents should be non-oxidised or protected.

Compounds of Formula (IX) are imidazoles and may be obtained by any ofthe procedures herein before described for preparing compounds ofFormula (I). In particular, an α-halo-ketone or other suitably activatedketones R₄COCH₂Hal (for compounds of Formula (IX) in which T₁ ishydrogen) or R₁COCH₂Hal (for compounds of Formula (IX) in which T₄ ishydrogen) may be reacted with an amidine of the formula R₂NH—C═NH,wherein R₂ is as defined in Formula (I), or a salt thereof, in an inertsolvent such as a halogenated hydrocarbon solvent, for instancechloroform, at a moderately elevated temperature, and, if necessary, inthe presence of a suitable condensation agent such as a base. Thepreparation of suitable a-halo-ketones is described in WO 91/19497.Suitable reactive esters include esters of strong organic acids such asa lower alkane sulphonic or aryl sulphonic acid, for instance, methaneor p-toluene sulphonic acid. The amidine is preferably used as the salt,suitably the hydrochloride salt, which may then be converted into thefree amidine in situ, by employing a two phase system in which thereactive ester is in an inert organic solvent such as chloroform, andthe salt is in an aqueous phase to which a solution of an aqueous baseis slowly added, in dimolar amount, with vigorous stirring. Suitableamidines may be obtained by standard methods, see for instance,Garigipati R, Tetrahedron Letters, 190, 31, 1989.

Compounds of Formula (I) may also be prepared by a process whichcomprises reacting a compound of Formula (IX), wherein T₁ is hydrogen,with an N-acyl heteroaryl salt, according to the method disclosed inU.S. Pat. No. 4,803,279, U.S. Pat. No. 4,719,218 and U.S. Pat. No.5,002,942, to give an intermediate in which the heteroaryl ring isattached to the imidazole nucleus and is present as a 1,4-dihydroderivative thereof, which intermediate may then be subjected tooxidative-deacylation conditions (Scheme II). The heteroaryl salt, forinstance a pyridinium salt, may be either preformed or, more preferably,prepared in situ by adding a substituted carbonyl halide (such as anacyl halide, an aroyl halide, an arylalkyl haloformate ester, or,preferably, an alkyl haloformate ester, such as acetyl bromide,benzoylchloride, benzyl chloroformate, or, preferably, ethyl chloroformate) to a solution of the compound of Formula (IX) in the heteroarylcompound R₁H or in an inert solvent such as methylene chloride to whichthe heteroaryl compound has been added. Suitable deacylating andoxidising conditions are described in U.S. Pat. Nos. 4,803,279,4,719,218 and 5,002,942, which references are hereby incorporated byreference in their entirety. Suitable oxidizing systems include sulfurin an inert solvent or solvent mixture, such as decalin, decalin anddiglyme, p-cymene, xylene or mesitylene, under reflux conditions, or,preferably, potassium t-butoxide in t-butanol with dry air or oxygen.

In a further process, illustrated in Scheme III below, compounds ofFormula (I) may be prepared by treating a compound of Formula (X)thermally or with the aid of a cyclising agent such as phosphorusoxychloride or phosphorus pentachloride (see Engel and Steglich, LiebigsAnn Chem, 1978, 1916 and Strzybny etal., J Org Chem, 1963, 28, 3381).Compounds of Formula (X) may be obtained, for instance, by acylating thecorresponding a-keto-amine with an activated formate derivative such asthe corresponding anhydride, under standard acylating conditionsfollowed by formation of the imine with R₂NH₂. The aminoketone may bederived from the parent ketone by examination and reduction and therequisite ketone may in turn be prepared by decarboxylation of thebeta-ketoester obtained from the condensation of an aryl (heteroaryl)acetic ester with the R₁COX component.

In Scheme IV illustrated below, two (2) different routes which useketone (formula XI) for preparing a compound of Formula (I). Aheterocyclic ketone (XI) is prepared by adding the anion of the alkylheterocycle such as 4-methyl-quinoline (prepared by treatment thereofwith an alkyl lithium, such as n-butyl lithium) to anN-alkyl-O-alkoxybenzamide, ester, or any other suitably activatedderivative of the same oxidation state. Alternatively, the anion may becondensed with a benzaldehyde, to give an alcohol which is then oxidisedto the ketone (XI).

In a further process, N-substituted compounds of Formula (I) may beprepared by treating the anion of an amide of Formula (XII):

R₁CH₂NR₂COH  (XII)

wherein R₁ and R₂ with:

(a) a nitrile of the Formula (XIII):

R₄CN  (XIII)

wherein R₄ is as hereinbefore defined, or

(b) an excess of an acyl halide, for instance an acyl chloride, of theFormula (XIV):

R₄COHal  (XIV)

wherein R₄ is as hereinbefore defined and Hal is halogen, or acorresponding anhydride, to give a bis-acylated intermediate which isthen treated with a source of ammonia, such as ammonium acetate.

One variation of this approach is illustrated in Scheme V above. Aprimary amine (R₂NH₂) is treated with a halomethyl heterocycle ofFormula R₁CH₂X to give the secondary amine which is then converted tothe amide by standard techniques. Alternatively the amide may beprepared as illustrated in scheme V by alkylation of the formamide withR₁CH₂X. Deprotonation of this amide with a strong amide base, such aslithium di-iso-propyl amide or sodium bis-(trimethylsilyl)amide,followed by addition of an excess of an aroyl chloride yields thebis-acylated compound which is then closed to an imidazole compound ofFormula (I), by heating in acetic acid containing ammonium acetate.Alternatively, the anion of the amide may be reacted with a substitutedaryl nitrile to produce the imidazole of Formula (I) directly.

The following description and schemes are further exemplification of theprocess as previously described above in Scheme I. Various pyrimidinealdehyde derivatives 6, 7 and 8 as depicted in scheme VI below, can beprepared by modification of the procedures of Bredereck et al. (Chem.Ber. 1964, 97, 3407) whose disclosure is incorporated by referenceherein. These pyrimidine aldehydes are then utilized as intermediates inthe synthesis as further described herein. The unprotected aminoaldehyde derivative, e.g. 8, can be somewhat unstable. Use of anacetolysis procedure, as described in Scheme VI, wherein the aldehyde 7is isolated as the acetamide derivative, (compound 3 is converted to 7,via the intermediate 4) and leads to a more stable compound for use inthe cycloaddition reaction to make compounds of Formula (I).

General acetolysis conditions, for such a reaction are employed and arewell known to those of skill in the art. Suitable conditions areexemplified, for instance in Example 83. In greater detail, the reactionemploys heating the 2-amino pyrimidine dialkoxy acetal with aceticanhydride in the presence of a catalytic amount of concentrated sulfuricacid, which simultaneously acetylates the amine and leads to theexchange of one of the alkoxy groups for an acetoxy group. The resultantcompound is converted to the aldehyde by deacetylation with a catalyticamount of an alkoxide salt and the corresponding alcohol solvent, e.g.Na+ methoxide and methanol. Alternatively, higher yields can be obtainedby first acetylating the amine with acetic anhydride and then affectingexchange by subsequent addition of concentrated sulfuric acid.

The reaction of imines with tosylmethyl isonitriles was first reportedby van Leusen (van Leusen, et al., J. Org. Chem. 1977, 42, 1153.)Reported were the following conditions: tert butyl amine(tBuNH₂) indimethoxyethane (DME), K₂CO₃ in MeOH, and NaH in DME. Uponre-examination of these conditions each was found to produce low yields.The desired product for instance,5-[(2-(1-methylamino)-pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazolewas isolated at yields less than 50%, using t-BuNH₂ in DME at roomtemperature, but a second pathway involving amine exchange to producethe t-butyl imine followed by reaction with the isocyanide 1 to producethe tBu imidazole was also operating. This will likely occur using anyprimary amine as a base. The secondary amines, while not preferred maybe used, but may also decompose the isonitrile slowly. Reactions willlikely require about 3 equivalents of amine to go to completion,resulting in approximately 50% isolated yields. Hindered secondaryamines (diisopropylamine) while usable are very slow and generally nottoo effective. Use of tertiary and aromatic amines, such as pyridine,and triethylamine gave no reaction under certain test conditions, butmore basic types such as DBU, and 4-dimethylamino pyridine (DMAP) whileslow, did produce some yields and hence may be suitable for use herein.

As depicted in Schemes VII and VIII below, the pyrimidine aldehydes ofScheme VI, can be condensed with a primary amine, to generate an imine,which may suitably be isolated or reacted in situ, with the desiredisonitrile in the presence of a variety of suitable bases, and solventsas described herein to afford the 5-(4-pyrimidinyl)-imidazoles, whereinR₂ and R₄ are as defined herein for Formula (I) compounds.

One preferred method for preparing compounds of Formula (I) is shownbelow in Scheme VII. The imines, prepared and isolated in a separatestep were often tars, which were hard to handle. The black color wasalso often carried over into the final product. The yield for making theimines varied, and environmentally less-acceptable solvents, such asCH₂Cl₂ were often used in their preparation.

This reaction, wherein p=2, requires a suitable base for the reaction toproceed. The reaction requires a base strong enough to deprotonate theisonitrile. Suitable bases include an amine, a carbonate, a hydride, oran alkyl or aryl lithium reagent; or mixtures thereof. Bases include,but are not limited to, potassium carbonate, sodium carbonate, primaryand secondary amines, such as morpholine, piperidine, pyrrolidine, andother non-nucleophilic bases.

Suitable solvents for use herein, include but are not limited toN,N-dimethylformamide (DMF), MeCN, halogenated solvents, such asmethylene chloride or chloroform, tetrahydrofuran (THF),dimethylsulfoxide (DMSO), alcohols, such as methanol or ethanol,benzene, or toluene, or DME. Preferably the solvent is DMF, DME, THF, orMeCN, more preferably DMF. Product isolation may generally beaccomplished by adding water and filtering the product as a cleancompound.

While not convenient for large scale work, addition of NaH to theisonitrile, perhaps with temperatures lower than 25° C. (in THF) arelikely needed. Additionally, BuLi has also been reported to be aneffective base for deprotonating tosyl benzylisonitriles at −50° C.(DiSanto, R.; Costi, R.; Massa, S.; Artico, M. Synth. Commun. 1995,25,795).

Various temperature conditions may be utilized depending upon thepreferred base. For instance, using tBuNH₂/DME and K₂CO₃/MeOH, reactionswere tried at 0, 25, 40, 60, and 80° C. At temperatures above 40° C.,the yields may drop to about 20%, although not much difference has beenseen between 0 and 25° C. Using K₂CO₃ in DMF, reactions were tried at 0°C. and 25° C., with virtually no difference in product, quality oryield. Consequently, temperature ranges below 0° C., and above 80° C.are contemplated as also being within the scope of this invention.Preferably, the temperature ranges are from about 0° C. to about 25° C.

As shown in Scheme VIII below, the imine is preferably formed in situ ina solvent. This preferred synthesis, is a process which occurs as aone-pot synthesis. Suitably, when the primary amine is utilized as asalt, such as in the dihydrochloride salt in the Examples, the reactionmay further include a base, such as potassium carbonate prior to theaddition of the isonitrile. Alternatively, the piperidine nitrogen maybe required to be protected as shown below. Reaction conditions, such assolvents, bases, temperatures, etc. are similar to those illustrated anddiscussed above for the isolated imine as shown in Scheme VIII. Oneskilled in the art would readily recognize that under somecircumstances, the in situ formation of the imine may requiredehydrating conditions, or may require acid catalysis.

The preferred method of synthesis for compounds of Formula (I) alsoprovides for a suitable and reliable method for introduction of anS(O)_(m)alkyl moiety on the pyrimidine (R₁ group) by using, forinstance, the 2-methylthio pyrimidine aldehyde derivative, as isdescribed in the Examples section. In scheme IX below, compound I (X═Smethyl), while a final product may also be used as a precursor, aspreviously noted to make further compounds of formula (I). In thisparticular instance the methylthio moiety is oxidized to the methylsulfinyl moiety which may additionally be further modified to asubstituted amino group.

Another embodiment of the present invention is the novel hydrolysis of2-5 thiomethylpyrimidine acetal to 2-thiomethylpyrimidine aldehyde, asshown in Scheme X below. Hydrolysis of the acetal to aldehyde usingvarious known reaction conditions, such as formic acid, did not producea satisfactory yield of the aldehyde, <13%) was obtained. The preferredsynthesis involves the use of AcOH (fresh) as solvent and concentratedH₂SO₄ under heating conditions, preferably a catalytic amount ofsulfuric acid. Heating conditions include temperatures from about 60 to85° C., preferably from about 70 to about 80° C. as higher temperaturesshow a darkening of the reaction mixture. After the reaction iscompleted the mixture is cooled to about room temperature and the aceticacid is removed. An example of this procedure is described herein asExample 100.

The final 2-aminopyrimidin-4-yl imidazole compounds of Formula (I), aswell as similar pyridine containing compounds can be prepared by one ofthree methods: 1) direct reaction of the 2-aminopyrimidine imine withthe isonitrile; 2) condensation of the 2-acetamidopyrimidine imine withthe isonitrile followed by removal of the acetamido group and 3)oxidation of the 2-methylthiopyrimidine derivative to the correspondingsulfoxide followed by displacement with the desired amine.

While these schemes herein are presented, for instance, with anoptionally substituted piperidine moiety for the resultant R₂ position,or a 4-fluoro phenyl for R₄, any suitable R₂ moiety or R₄ moiety may beadded in this manner if it can be prepared on the primary amine.Similarly, any suitable R₄ can be added via the isonitrile route.

The compounds of Formula (II), in Scheme I, may be prepared by themethods of van Leusen et al., supra. For example a compound of theFormula (II) may be prepared by dehydrating a compound of the Formula(IV)-Scheme I, wherein Ar, R₄ and p are as defined herein.

Suitable dehydrating agents include phosphorus oxychloride, oxalylchloride, thionyl chloride, phosgene, or tosyl chloride in the presenceof a suitable base such as triethylamine or diisopropylethylamine, orsimilar bases, etc. such as pyridine. Suitable solvents are dimethoxyether, tetrahydrofuran, or halogenated solvents, preferably THF. Thereaction is most efficent when the reaction temperatures are keptbetween −10° C. and 0° C. At lower temperatures incomplete reactionoccurs and at higher temperatures, the solution turns dark and theproduct yield drops.

The compounds of formula (IV)-Scheme I may be prepared by reacting acompound of the formula (V)-Scheme I, R₄CHO where R₄ is as definedherein, with ArS(O)_(p)H and formamide with or without water removal,preferably under dehydrating conditions, at ambient or elevatedtemperature e.g. 30° to 150°, conveniently at reflux, optionally in thepresence of an acid catalyst. Alternatively trimethysilylchloride can beused in place of the acid catalyst. Examples of acid catalysts includecamphor-10-sulphonic acid, formic acid, p-toluenesulphonic acid,hydrogen chloride or sulphuric acid.

An optimal method of making an isonitrile of Formula (II) is illustratedbelow, in Scheme XI, and in the Examples section, Example 85 herein.

The conversion of the substituted aldehyde to the tosylbenzyl formamidemay be accomplished by heating the aldehyde, 1-Scheme XI, with an acid,such as p-toluenesulfonic acid, formic acid or camphorsulfonic acid;with formamide and p-toluenesulfinic acid [under reaction conditions ofabout 60° C. for about 24 hours]. Preferably, no solvent is used. Thereaction, may give poor yields (<30%) when solvents, such as DMF, DMSO,toluene, acetonitrile, or excess formamide are used. Temperatures lessthan 60° C. are generally poor at producing the desired product, andtemperatures in excess of 60° C. may produce a product which decomposes,or obtain a benzylic bis-formamide 2-Scheme XI.

Another embodiment of the present invention is the synthesis of thetosyl benzyl formamide compound, achieved by reacting the bisformamideintermediate 2-Scheme XI with p-toluenesulfinic acid. In this preferredroute, preparation of the bis-formamide from the aldehyde isaccomplished by heating the aldehyde with formamide, in a suitablesolvent with acid catalysis. Suitable solvents are toluene,acetonitrile, DMF, and DMSO or mixtures thereof. Acid catalysts, arethose well known in the art, and include but are not limited to hydrogenchloride, p-toluenesulfonic acid, camphorsulfonic acid, and otheranhydrous acids. The reaction can be conducted at temperatures rangingfrom about 25° C. to 110° C., preferably about 50° C., suitably forabout 4 to about 5 hours, longer reaction times are also acceptable.Product decomposition and lower yields may be observed at highertemperatures (>70° C.) at prolonged reactions times. Complete conversionof the product generally requires water removal from the reactionmixture.

Preferred conditions for converting a bis-formamide derivative to thetosyl benzyl formamide are accomplished by heating the bisformamide in asuitable solvent with an acid catalyst and p-toluenesulfinic acid.Solvents for use in this reaction include but are not limited totoluene, and acetonitrile or mixtures thereof. Additional mixtures ofthese solvents with DMF, or DMSO may also be used but may result inlower yields. Temperatures may range from about 30° C. to about 100° C.Temperatures lower than 40° C. and higher than 60° C. are not preferredas the yield and rate decreases. Preferably the range is from about 40to 60° C., most preferably about 50° C. The optimal time is about 4 to 5hours, although it may be longer. Preferably, acids used include but arenot limited to, toluenesulfonic acid, camphorsulfonic acid, and hydrogenchloride and other anhydrous acids. Most preferably the bisformamide isheated in toluene:acetonitrile in a 1:1 ratio, with p-toluenesulfinicacid and hydrogen chloride.

Another embodiment of the present invention is the preferred syntheticroute for synthesis of the tosylbenzyl formamide compound which isaccomplished using a one-pot procedure. This process first converts thealdehyde to the bis-formamide derivative and subsequently reacts thebis-formamide derivative with toluenesulfinic acid. This procedurecombines the optimized conditions into a single, efficient process. Highyields, >90% of the aryl (tosyl) benzylformamide may be obtained in sucha manner.

Preferred reaction conditions employ a catalyst, such as trimethylsilylchloride (TMSCl), in a preferred solvent, toluene:acetonitrile,preferably in a 1:1 ratio. A reagent, such as TMSCl, is preferred whichreacts with water produced therein and at the same time produceshydrogen chloride to catalyze the reaction. Also preferred is use ofhydrogen chloride and p-toluenesulfonic acid. Therefore, three suitablereaction conditions for use herein include 1) use of a dehydrating agentwhich also provides hydrogen chloride, such as TMSCl or p-toluenesulfinic acid; or by 2) use of a suitable dehydrating agent and asuitable source of acid source, such as but not limited to,camphorsulfonic acid, hydrogen chloride or p-toluenesulfonic acid; and3) alternative dehydrating conditions, such as the azeotropic removal ofwater, and using an acid catalyst and p-toluene sulfinic acid.

Compounds of the formula (II) where p is 2 may also be prepared byreacting in the presence of a strong base a compound of the formula(VI)-Scheme I, R₄CH₂NC with a compound of the formula (VII)-Scheme I,ArSO₂L₁ wherein R₄ and Ar are as defined herein and L₁ is a leavinggroup such as halo, e.g. fluoro. Suitable strong bases include, but arenot limited to, alkyl lithiums such as butyl lithium or lithiumdiisopropylamide (Van Leusen et al., Tetrahedron Letters, No. 23,2367-68 (1972)).

The compounds of formula (VI)-Scheme I may be prepared by reacting acompound of the formula (VIII)-Scheme I, R₄CH₂NH₂ with an alkyl formate(e.g. ethylformate) to yield an intermediate amide which can beconverted to the desired isonitrile by reacting with well knowndehydrating agent, such as but not limited to oxalyl chloride,phosphorus oxychloride or tosyl chloride in the presence of a suitablebase such as triethylamine.

Alternatively a compound of the formula (VIII)-Scheme I may be convertedto a compound of the formula (VI)-Scheme I by reaction with chloroformand sodium hydroxide in aqueous dichloromethane under phase transfercatalysis.

The compounds of the formula (III)-Scheme I may be prepared by reactinga compound of the formula R₁CHO with a primary amine R₂NH₂.

The amino compounds of the formula (VIII)-Scheme I are known or can beprepared from the corresponding alcohols, oximes or amides usingstandard functional group interconversions.

Suitable protecting groups for use with hydroxyl groups and theimidazole nitrogen are well known in the art and described in manyreferences, for instance, Protecting Groups in Organic Synthesis, GreeneT W, Wiley-Interscience, New York, 1981. Suitable examples of hydroxylprotecting groups include silyl ethers, such as t-butyldimethyl ort-butyldiphenyl, and alkyl ethers, such as methyl connected by an alkylchain of variable link, (CR₁₀R₂₀)_(n). Suitable examples of imidazolenitrogen protecting groups include tetrahydropyranyl.

Pharmaceutically acid addition salts of compounds of Formula (I) may beobtained in known manner, for example by treatment thereof with anappropriate amount of acid in the presence of a suitable solvent.

METHODS OF TREATMENT

The compounds of Formula (I) or a pharmaceutically acceptable saltthereof can be used in the manufacture of a medicament for theprophylactic or therapeutic treatment of any disease state in a human,or other mammal, which is exacerbated or caused by excessive orunregulated cytokine production by such mammal's cell, such as but notlimited to monocytes and/or macrophages.

Compounds of Formula (I) are capable of inhibiting proinflammatorycytokines, such as IL-1, IL-6, IL-8 and TNF and are therefore of use intherapy. IL-1, IL-6, IL-8 and TNF affect a wide variety of cells andtissues and these cytokines, as well as other leukocyte-derivedcytokines, are important and critical inflammatory mediators of a widevariety of disease states and conditions. The inhibition of thesepro-inflammatory cytokines is of benefit in controlling, reducing andalleviating many of these disease states.

Accordingly, the present invention provides a method of treating acytokine-mediated disease which comprises administering an effectivecytokine-interfering amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In particular, compounds of Formula (I) or a pharmaceutically acceptablesalt thereof are of use in the prophylaxis or therapy of any diseasestate in a human, or other mammal, which is exacerbated by or caused byexcessive or unregulated IL-1, IL-8 or TNF production by such mammal'scell, such as, but not limited to, monocytes and/or macrophages.

Compounds of Formula (I) are capable of inhibiting inducibleproinflammatory proteins, such as COX-2, also referred to by many othernames such as prostaglandin endoperoxide synthase-2 (PGHS-2) and aretherefore of use in therapy. These proinflammatory lipid mediators ofthe cyclooxygenase (CO) pathway are produced by the inducible COX-2enzyme. Regulation, therefore of COX-2 which is responsible for thethese products derived from arachidonic acid, such as prostaglandinsaffect a wide variety of cells and tissues are important and criticalinflammatory mediators of a wide variety of disease states andconditions. Expression of COX-1 is not effected by compounds of Formula(I). This selective inhibition of COX-2 may alleviate or spareulcerogenic liability associated with inhibition of COX-1 therebyinhibiting prostoglandins essential for cytoprotective effects. Thusinhibition of these pro-inflammatory mediators is of benefit incontrolling, reducing and alleviating many of these disease states. Mostnotably these inflammatory mediators, in particular prostaglandins, havebeen implicated in pain, such as in the sensitization of pain receptors,or edema. This aspect of pain management therefore includes treatment ofneuromuscular pain, headache, cancer pain, and arthritis pain. Compoundsof Formula (I) or a pharmaceutically acceptable salt thereof, are of usein the prophylaxis or therapy in a human, or other mammal, by inhibitionof the synthesis of the COX-2 enzyme.

Accordingly, the present invention provides a method of inhibiting thesynthesis of COX-2 which comprises administering an effective amount ofa compound of Formula (I) or a pharmaceutically acceptable salt thereof.The present invention also provides for a method of prophylaxistreatment in a human, or other mammal, by inhibition of the synthesis ofthe COX-2 enzyme.

Accordingly, in another aspect, this invention relates to a method ofinhibiting the production of IL-1 in a mammal in need thereof whichcomprises administering to said mammal an effective amount of a compoundof Formula (I) or a pharmaceutically acceptable salt thereof.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis, osteoarthritis, stroke, endotoxemiaand/or toxic shock syndrome, other acute or chronic inflammatory diseasestates such as the inflammatory reaction induced by endotoxin orinflammatory bowel disease, tuberculosis, atherosclerosis, muscledegeneration, multiple sclerosis, cachexia, bone resorption, psoriaticarthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumaticarthritis, rubella arthritis and acute synovitis. Recent evidence alsolinks IL-1 activity to diabetes, pancreatic β cells and Alzheimer'sdisease.

In a further aspect, this invention relates to a method of inhibitingthe production of TNF in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof.

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions, sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, stroke, cerebral malaria, chronic pulmonary inflammatorydisease, silicosis, pulmonary sarcoisosis, bone resorption diseases,such as osteoporosis, reperfusion injury, graft vs. host reaction,allograft rejections, fever and myalgias due to infection, such asinfluenza, cachexia secondary to infection or malignancy, cachexiasecondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDSrelated complex), keloid formation, scar tissue formation, Crohn'sdisease, ulcerative colitis and pyresis.

Compounds of Formula (I) are also useful in the treatment of viralinfections, where such viruses are sensitive to upregulation by TNF orwill elicit TNF production in vivo. The viruses contemplated fortreatment herein are those that produce TNF as a result of infection, orthose which are sensitive to inhibition, such as by decreasedreplication, directly or indirectly, by the TNF inhibiting-compounds ofFormula (I). Such viruses include, but are not limited to HIV-1, HIV-2and HIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpesgroup of viruses, such as but not limited to, Herpes Zoster and HerpesSimplex. Accordingly, in a further aspect, this invention relates to amethod of treating a mammal afflicted with a human immunodeficiencyvirus (HIV) which comprises administering to such mammal an effectiveTNF inhibiting amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

Compounds of Formula (I) may also be used in association with theveterinary treatment of mammals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to, lentivirus infectionssuch as, equine infectious anaemia virus, caprine arthritis virus, visnavirus, or maedi virus or retrovirus infections, such as but not limitedto feline immunodeficiency virus (FIV), bovine immunodeficiency virus,or canine immunodeficiency virus or other retroviral infections.

The compounds of Formula (I) may also be used topically in the treatmentor prophylaxis of topical disease states mediated by or exacerbated byexcessive cytokine production, such as by IL-1 or TNF respectively, suchas inflamed joints, eczema, psoriasis and other inflammatory skinconditions such as sunburn; inflammatory eye conditions includingconjunctivitis; pyresis, pain and other conditions associated withinflammation.

Compounds of Formula (I) have also been shown to inhibit the productionof IL-8 (Interleukin-8, NAP). Accordingly, in a further aspect, thisinvention relates to a method of inhibiting the production of IL-8 in amammal in need thereof which comprises administering to said mammal aneffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

There are many disease states in which excessive or unregulated IL-8production is implicated in exacerbating and/or causing the disease.These diseases are characterized by massive neutrophil infiltration suchas, psoriasis, inflammatory bowel disease, asthma, cardiac and renalreperfusion injury, adult respiratory distress syndrome, thrombosis andglomerulonephritis. All of these diseases are associated with increasedIL-8 production which is responsible for the chemotaxis of neutrophilsinto the inflammatory site. In contrast to other inflammatory cytokines(IL-1, TNF, and IL-6), IL-8 has the unique property of promotingneutrophil chemotaxis and activation. Therefore, the inhibition of IL-8production would lead to a direct reduction in the neutrophilinfiltration.

The compounds of Formula (I) are administered in an amount sufficient toinhibit cytokine, in particular IL-1, IL-6, IL-8 or TNF, production suchthat it is regulated down to normal levels, or in some case to subnormallevels, so as to ameliorate or prevent the disease state. Abnormallevels of IL-1, IL-6, IL-8 or TNF, for instance in the context of thepresent invention, constitute: (i) levels of free (not cell bound) IL-1,IL-6, IL-8 or TNF greater than or equal to 1 picogram per ml; (ii) anycell associated IL-1, IL-6, IL-8 or TNF; or (iii) the presence of IL-1,IL-6, IL-8 or TNF mRNA above basal levels in cells or tissues in whichIL-1, IL-6, IL-8 or TNF, respectively, is produced.

The discovery that the compounds of Formula (I) are inhibitors ofcytokines, specifically IL-1, IL-6, IL-8 and TNF is based upon theeffects of the compounds of Formulas (I) on the production of the IL-1,IL-8 and TNF in in vitro assays which are described herein.

As used herein, the term “inhibiting the production of IL-1 (IL-6, IL-8or TNF)” refers to:

a) a decrease of excessive in vivo levels of the cytokine (IL-1, IL-6,IL-8 or TNF) in a human to normal or sub-normal levels by inhibition ofthe in vivo release of the cytokine by all cells, including but notlimited to monocytes or macrophages;

b) a down regulation, at the genomic level, of excessive in vivo levelsof the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal orsub-normal levels;

c) a down regulation, by inhibition of the direct synthesis of thecytokine (IL-1, IL-6, IL-8 or TNF) as a postranslational event; or

d) a down regulation, at the translational level, of excessive in vivolevels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal orsub-normal levels.

As used herein, the term “TNF mediated disease or disease state” refersto any and all disease states in which TNF plays a role, either byproduction of TNF itself, or by TNF causing another monokine to bereleased, such as but not limited to IL-1, IL-6 or IL-8. A disease statein which, for instance, IL-1 is a major component, and whose productionor action, is exacerbated or secreted in response to TNF, wouldtherefore be considered a disease stated mediated by TNF.

As used herein, the term “cytokine” refers to any secreted polypeptidethat affects the functions of cells and is a molecule which modulatesinteractions between cells in the immune, inflammatory or hematopoieticresponse. A cytokine includes, but is not limited to, monokines andlymphokines, regardless of which cells produce them. For instance, amonokine is generally referred to as being produced and secreted by amononuclear cell, such as a macrophage and/or monocyte. Many other cellshowever also produce monokines, such as natural killer cells,fibroblasts, basophils, neutrophils, endothelial cells, brainastrocytes, bone marrow stromal cells, epideral keratinocytes andB-lymphocytes. Lymphokines are generally referred to as being producedby lymphocyte cells. Examples of cytokines include, but are not limitedto, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8),Tumor Necrosis Factor-alpha (TNF-α) and Tumor Necrosis Factor beta(TNF-β).

As used herein, the term “cytokine interfering” or “cytokine suppressiveamount” refers to an effective amount of a compound of Formula (I) whichwill cause a decrease in the in vivo levels of the cytokine to normal orsub-normal levels, when given to a patient for the prophylaxis ortreatment of a disease state which is exacerbated by, or caused by,excessive or unregulated cytokine production.

As used herein, the cytokine referred to in the phrase “inhibition of acytokine, for use in the treatment of a HIV-infected human” is acytokine which is implicated in (a) the initiation and/or maintenance ofT cell activation and/or activated T cell-mediated HIV gene expressionand/or replication and/or (b) any cytokine-mediated disease associatedproblem such as cachexia or muscle degeneration.

As TNF-β (also known as lymphotoxin) has close structural homology withTNF-α (also known as cachectin) and since each induces similar biologicresponses and binds to the same cellular receptor, both TNF-α and TNF-βare inhibited by the compounds of the present invention and thus areherein referred to collectively as “TNF” unless specifically delineatedotherwise.

In order to use a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in therapy, it will normally be Formulated intoa pharmaceutical composition in accordance with standard pharmaceuticalpractice. This invention, therefore, also relates to a pharmaceuticalcomposition comprising an effective, non-toxic amount of a compound ofFormula (I) and a pharmaceutically acceptable carrier or diluent.

Compounds of Formula (I), pharmaceutically acceptable salts thereof andpharmaceutical compositions incorporating such may conveniently beadministered by any of the routes conventionally used for drugadministration, for instance, orally, topically, parenterally or byinhalation. The compounds of Formula (I) may be administered inconventional dosage forms prepared by combining a compound of Formula(I) with standard pharmaceutical carriers according to conventionalprocedures. The compounds of Formula (I) may also be administered inconventional dosages in combination with a known, second therapeuticallyactive compound. These procedures may involve mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation. It will be appreciated that the form and character of thepharmaceutically acceptable character or diluent is dictated by theamount of active ingredient with which it is to be combined, the routeof administration and other well-known variables. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the Formulation and not deleterious to the recipient thereof.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly, the carrier or diluent may includetime delay material well known to the art, such as glycerylmono-stearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 g. When a liquid carrier is used,the preparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule or nonaqueousliquid suspension.

Compounds of Formula (I) may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof Formula (I) externally to the epidermis or the buccal cavity and theinstillation of such a compound into the ear, eye and nose, such thatthe compound does not significantly enter the blood stream. In contrast,systemic administration refers to oral, intravenous, intraperitoneal andintramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as liniments, lotions, creams, ointmentsor pastes, and drops suitable for administration to the eye, ear ornose. The active ingredient may comprise, for topical administration,from 0.001% to 10% w/w, for instance from 1% to 2% by weight of theFormulation. It may however comprise as much as 10% w/w but preferablywill comprise less than 5% w/w, more preferably from 0.1% to 1% w/w ofthe Formulation.

Lotions according to the present invention include those suitable forapplication to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those for the preparation of drops. Lotions orliniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol or acetone,and/or a moisturizer such as glycerol or an oil such as castor oil orarachis oil.

Creams, ointments or pastes according to the present invention aresemi-solid Formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous fluid, with the aid of suitable machinery,with a greasy or non-greasy base. The base may comprise hydrocarbonssuch as hard, soft or liquid paraffin, glycerol, beeswax, a metallicsoap; a mucilage; an oil of natural origin such as almond, corn,arachis, castor or olive oil; wool fat or its derivatives or a fattyacid such as steric or oleic acid together with an alcohol such aspropylene glycol or a macrogel. The Formulation may incorporate anysuitable surface active agent such as an anionic, cationic or non-ionicsurfactant such as a sorbitan ester or a polyoxyethylene derivativethereof. Suspending agents such as natural gums, cellulose derivativesor inorganic materials such as silicaceous silicas, and otheringredients such as lanolin, may also be included.

Drops according to the present invention may comprise sterile aqueous oroily solutions or suspensions and may be prepared by dissolving theactive ingredient in a suitable aqueous solution of a bactericidaland/or fungicidal agent and/or any other suitable preservative, andpreferably including a surface active agent. The resulting solution maythen be clarified by filtration, transferred to a suitable containerwhich is then sealed and sterilized by autoclaving or maintaining at98-100° C. for half an hour. Alternatively, the solution may besterilized by filtration and transferred to the container by an aseptictechnique. Examples of bactericidal and fungicidal agents suitable forinclusion in the drops are phenylmercuric nitrate or acetate (0.002%),benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).Suitable solvents for the preparation of an oily solution includeglycerol, diluted alcohol and propylene glycol.

Compounds of formula (I) may be administered parenterally, that is byintravenous, intramuscular, subcutaneous intranasal, intrarectal,intravaginal or intraperitoneal administration. The subcutaneous andintramuscular forms of parenteral administration are generallypreferred. Appropriate dosage forms for such administration may beprepared by conventional techniques. Compounds of Formula (I) may alsobe administered by inhalation, that is by intranasal and oral inhalationadministration. Appropriate dosage forms for such administration, suchas an aerosol Formulation or a metered dose inhaler, may be prepared byconventional techniques.

For all methods of use disclosed herein for the compounds of Formula(I), the daily oral dosage regimen will preferably be from about 0.1 toabout 80 mg/kg of total body weight, preferably from about 0.2 to 30mg/kg, more preferably from about 0.5 mg to 15 mg. The daily parenteraldosage regimen about 0.1 to about 80 mg/kg of total body weight,preferably from about 0.2 to about 30 mg/kg, and more preferably fromabout 0.5 mg to 15 mg/kg. The daily topical dosage regimen willpreferably be from 0.1 mg to 150 mg, administered one to four,preferably two or three times daily. The daily inhalation dosage regimenwill preferably be from about 0.01 mg/kg to about 1 mg/kg per day. Itwill also be recognized by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound of Formula (I)or a pharmaceutically acceptable salt thereof will be determined by thenature and extent of the condition being treated, the form, route andsite of administration, and the particular patient being treated, andthat such optimums can be determined by conventional techniques. It willalso be appreciated by one of skill in the art that the optimal courseof treatment, i.e., the number of doses of a compound of Formula (I) ora pharmaceutically acceptable salt thereof given per day for a definednumber of days, can be ascertained by those skilled in the art usingconventional course of treatment determination tests.

The invention will now be described by reference to the followingbiological examples which are merely illustrative and are not to beconstrued as a limitation of the scope of the present invention.

BIOLOGICAL EXAMPLES

The cytokine-inhibiting effects of compounds of the present inventionwere determined by the following in vitro assays:

Interleukin-1 (IL-1)

Human peripheral blood monocytes were isolated and purified from eitherfresh blood preparations from volunteer donors, or from blood bank buffycoats, according to the procedure of Colotta et al, J Immunol, 132, 936(1984). These monocytes (1×10⁶) were plated in 24-well plates at aconcentration of 1-2 million/ml per well. The cells were allowed toadhere for 2 hours, after which time non-adherent cells were removed bygentle washing. Test compounds were then added to the cells for 1 hbefore the addition of lipopolysaccharide (50 ng/ml), and the cultureswere incubated at 37° C. for an additional 24 h. At the end of thisperiod, culture super-natants were removed and clarified of cells andall debris. Culture supernatants were then immediately assayed for IL-1biological activity, either by the method of Simon et al., J. Immunol.Methods, 84, 85, (1985) (based on ability of IL-1 to stimulate aInterleukin 2 producing cell line (EL-4) to secrete IL-2, in concertwith A23187 ionophore) or the method of Lee et al., J. ImmunoTherapy, 6(1), 1-12 (1990) (ELISA assay). The compounds of Formula (I), asevidenced by Examples 1 to 24 were shown to be inhibitors of in vitroIL-1 produced by human monocytes.

Tumour Necrosis Factor (TNF):

Human peripheral blood monocytes were isolated and purified from eitherblood bank buffy coats or plateletpheresis residues, according to theprocedure of Colotta, R. et al., J Immunol, 132(2), 936 (1984). Themonocytes were plated at a density of 1×10⁶ cells/ml medium/well in24-well multi-dishes. The cells were allowed to adhere for 1 hour afterwhich time the supernatant was aspirated and fresh medium (1 ml,RPMI-1640, Whitaker Biomedical Products, Whitaker, Calif.) containing 1%fetal calf serum plus penicillin and streptomycin (10 units/ml) added.The cells were incubated for 45 minutes in the presence or absence of atest compound at 1 nM-10 mM dose ranges (compounds were solubilized indimethyl sulfoxide/ethanol, such that the final solvent concentration inthe culture medium was 0.5% dimethyl sulfoxide/0.5% ethanol). Bacteriallipopoly-saccharide (E. coli 055:B5 [LPS] from Sigma Chemicals Co.) wasthen added (100 ng/ml in 10 ml phosphate buffered saline) and culturesincubated for 16-18 hours at 37° C. in a 5% CO₂ incubator. At the end ofthe incubation period, culture supernatants were removed from the cells,centrifuged at 3000 rpm to remove cell debris. The supernatant was thenassayed for TNF activity using either a radio-immuno or an ELISA assay,as described in WO 92/10190 and by Becker et al., J Immunol, 1991, 147,4307. The compounds of Formula (I), as evidenced by Examples 1 to 24were shown to be inhibitors of in vitro TNF produced by human monocytes.

IL-1 and TNF inhibitory activity does not seem to correlate with theproperty of the compounds of Formula (I) in mediating arachidonic acidmetabolism inhibition. Further the ability to inhibit production ofprostaglandin and/or leukotriene synthesis, by nonsteroidalanti-inflammatory drugs with potent cyclooxygenase and/or lipoxygenaseinhibitory activity does not mean that the compound will necessarilyalso inhibit TNF or IL-1 production, at non-toxic doses.

Interleukin-8 (IL-8):

Primary human umbilical cord endothelial cells (HUVEC) (Cell Systems,Kirland, Wash.) are maintained in culture medium supplemented with 15%fetal bovine serum and 1% CS-HBGF consisting of aFGF and heparin. Thecells are then diluted 20-fold before being plated (250 μl) intogelating coated 96-well plates. Prior to use, culture medium arereplaced with fresh medium (200 μl). Buffer or test compound (25 μl, atconcentrations between 1 and 10 μM) is then added to each well inquadruplicate wells and the plates incubated for 6 h in a humidifiedincubator at 37° C. in an atmosphere of 5% CO₂. At the end of theincubation period, supernatant is removed and assayed for IL-8concentration using an IL-8 ELISA kit obtained from R&D Systems(Minneapolis, Minn.). All data is presented as mean value (ng/ml) ofmultiple samples based on the standard curve. IC₅₀'s where appropriateare generated by non-linear regression analysis.

Cytokine Specific Binding Protein Assay

A radiocompetitive binding assay was developed to provide a highlyreproducible primary screen for structure-activity studies. This assayprovides many advantages over the conventional bioassays which utilizefreshly isolated human monocytes as a source of cytokines and ELISAassays to quantify them. Besides being a much more facile assay, thebinding assay has been extensively validated to highly correlate withthe results of the bioassay. A specific and reproducible cytokineinhibitor binding assay was developed using soluble cystosolic fractionfrom THP.1 cells and a radiolabeled compound. For instance, a suitableradiolabeled compound of this cytokine inhibitor class is4-(Fluorophenyl)-2-(4-hydroxyphenyl-3,5-t₂)-5-(4-pyridyl)imidazole. Inbrief, the THP.1 cytosol was routinely prepared from cell lysateobtained by nitrogen cavitation followed by a 10 K×g low speed and a 100K×g high speed centrifugation, the supernatant of which was designatedas the cytosolic fraction. THP.1 cytosol was incubated withappropriately diluted radioligand at room temperature for apre-determined time to allow the binding to achieve equilibrium. Thesample was added to a G-10 column and eluted with 20 mm TRN, 50mMb-mercaptoethanol, NaN₃ The fraction encompassing the void volume wascollected and the radioactivity was assessed by liquid scintillationcounting. This was determined to reflect bound radioligand since theradioactive signal was abrogated by the presence of excess cold ligandin the incubation mixture or when there was no cytosolic fractionpresent. Compounds of Formula (I) at various doses were added to thebinding assay to achieve inhibition of binding of the radiolabel. IC₅₀sas well as Ki values were determined by regression analysis andscatchard plot analysis respectively. There is generally excellentcorrelation between the IC₅₀ of compounds tested in both the bindingassay and the bioassay and can be used interchangeably in many cases.

U.S. patent application Ser. No. 08/123175 Lee et al., filed September1993 whose disclosure is incorporated by reference herein in its entireydescribes the above noted method for screening drugs to identifycompounds which interact with and bind to the cytokine specific bindingprotein (hereinafter CSBP). However, for purposes herein the bindingprotein may be in isolated form in solution, or in immobilized form, ormay be genetically engineered to be expressed on the surface ofrecombinant host cells such as in phage display system or as fusionproteins. Alternatively, whole cells or cytosolic fractions comprisingthe CSBP may be employed in the creening protocol. Regardless of theform of the binding protein, a plurality of compounds are contacted withthe binding protein under conditions sufficient to form acompound/binding protein complex and compound capable of forming,enhancing or interfering with said complexes are detected.

More specifically, the Binding Assay is performed as follows:

MATERIALS

Incubation buffer: 20 mM Tris, 1 mM MgCl₂, 20 mM Hepes, 0.02% NaN₃,store at 4° C. Elution buffer: 20 mM Tris, 50 mM 2-mercaptoethanol,NaN₃, store at 4° C. G-10 Sephadex: add 100 g Sephadex G-10 (Pharmacia,Uppsala, Sweden) to 400 mL dd H₂O and allow to swell at room temperaturefor 2 hours. Decant fines and wash 3 times. Add NaN₃ and qs with dd H₂Oto 500 mLs and store at 4° C.

Assemble Columns: Straw column, filter frit and tip (Kontes, SP420160-000, 420162-002). Lowsorb tubes (Nunc) used in binding reaction.THP.1 cytosol spun at 15000 rpm for 5 min to clarify. THP.1 cytosolprepared by hypnotic treatment of cells and lysis by decompression innitrogen. Nuclei and membrane fragments removed by differentialcentrifugation (10,000 g for 1 hour and 100,000 g for 1 hour).

Compounds: Non-radioactive Compound I with corresponding EtOH control(dilutions made in incubation buffer) and ³H-Compound I (dilutions inincubation buffer)

METHOD

A. Column Preparation

1. Begin 30 min before anticipated elution of reaction mixture.

2. Add 3 mL of G-10 slurry to column for bed vol of 1.5 ml.

3. Rinse with 7 mL elution buffer (fill to top of column)

4. Cut columns down to size.

B. Sample Incubation

1. 15 min incubation at 4° C.

2. Binding reaction mixture; 100 μL cytosol, 10 uL cold Compound I orEtOH control, 10 μL ³H-Compound I (molar concentration depends on natureof study).

3. “Free” control=100 μL incubation buffer in lieu of cytosolpreparation.

C. Sample Elution

1. Elute at 4° C.

2. Add total reaction volume to G-10 column.

3. Add 400 μL elution buffer to column and discard eluate.

4. Add 500 μL elution buffer to column, collecting eluted volume in 20ml scintillation vial.

5. Add 15 mL Ready Safe scintillation fluid.

6. Vortex and count in liquid scintillation counter for 5 minutes.Include a “total input counts control” (10 μL of labeled ligand).

D. Data Analysis

1. Plot DPMS as ouptut in graphic form and analyze by regressionanalysis and “Lundon ligand binding” software for the determination ofIC 50 and Kd/Ki respectively.

2. Rank order the IC50s of the tested compounds in the bioassay andcompare to that generated by the binding assay and establish acorrelation curve.

The binding assay was further validated by the following criteria: THP.1cytosol demonstrated saturable and specific binding of the radiolabeledcompound.

Preparation of4-(Fluorophenyl)-2-(4-hydroxyphenyl-3,5-t₂)-5-(4-pyridyl)imidazole,(Compound I).

A 2.9 mg (0.0059 mmol) portion of2-(3,5-Dibromo-4-hydroxyphenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole,Compound I(p), was dissolved in 0.95 mL of dry DMF and 0.05 mL oftriethylamine in a 2.4 mL round bottom flask equipped with a smallmagnetic stirring bar. A 1.7 mg portion of 5% Pd/C (Engelhard lot 28845)was added, and the flask was attached to the stainless steel tritiummanifold. The mixture was degassed through four freeze-pump-thaw cycles,then tritium gas (5.3 Ci, 0.091 mmol) was introduced. The reactionmixture was allowed to warm to room temperature and was stirredvigorously for 20 h. The mixture was frozen in liquid nitrogen, theremaining tritium gas (2.4 Ci) was removed, and the flask was removedfrom the manifold. The reaction mixture was transferred, using 3×1 mL ofmethanol as rinsings, into a 10 mL round bottom flask, and the solventswere removed by static vacuum transfer. A 1.5 mL portion of methanol wasadded to the residue, then removed by static vacuum transfer. The latterprocess was repeated. Finally, the residue was suspended in 1.5 mL ofethanol and filtered through a syringe-tip Millipore filter (0.45micron), along with 3×ca. 1 mL ethanol rinsings. The total filtratevolume was determined to be 3.9 mL, and the total radioactivity, 94.2mCi. Solution was determined to be 3.9 mL, and the total radioactivity,94.2 mCi. HPLC analysis of filtrate (Partisil 5 ODS-3, 4.6 mm I.D.×25cm, 1 mL/min of 70:30:01 water/acetonitrile/trifluoroacetic acid,Radiomatic Flo-One Beta radio detector with 3 mL/min of Ecoscint-Hcocktail through a 0.75 mL cell) showed the presence of Compound I(R_(t)=60 min. ca. 37% of total radioactivity), and a discreteintermediate presumed to be the monobromo derivative Compound Ia(R_(t)=11.8 min, ca. 9%).

The filtrate solution was evaporated to near dryness with a stream ofnitrogen, and the residue was dissolved in about 1.2 mL of the HPLCmobile phase. The solution was separated by HPLC as shown below, and thepeaks corresponding to Compounds I and Ia and SB collected separately.

HPLC Method Column Altex Ultrasphere 10 mm I.D. × 25 cm Mobile Phase70:30:0.1 water/acetonitrile/trifluoroacetic acid Flow Rate 5 mL/min UVdetection 210 nm Injection Volumes 0.05-0.4 m: Retention Times 7.8 minCompound I 24 min Compound Ia

The pooled Compound I fractions totaled 32 mL in volume and theradioactive concentration was 1.52 mCi/mL (total 48.6 mCi). The pooledSB Compound Ia [³H] fractions (totaling 10.1 mCi) were evaporated todryness and the residue was transferred quantitatively into a glass vialusing 3.8 mL of absolute ethanol for further analysis.

An 8 mL (12.2 mCi) portion of Compound I was evaporated to dryness invacuo at <35° C., then redissolved in 0.5 mL of mobile phase. The wholevolume was injected into the HPLC system described above, and theappropriate peak was collected. Evaporation of the collected eluate invacuo at <35° C. and transfer of the yellow residue into a vial withabsolute ethanol provided a solution (3.8 mL, 2.44 mCi/mL) of CompoundI. The portion of this solution used for NMR analyses was firstevaporated to dryness using stream of nitrogen then taken up in CD₃OD.

Analysis of4-(4-Fluorophenyl)-2-(4-hydroxyphenyl-3,5-t₂)-5-(4-pyridyl)imidazole,Compound I.

Radiochemical Purity by HPLC Method Column Ultrasphere Octyl, 5 mm, 4.6mm I.D. × 25 cm, Beckman Mobile Phase 350:150:0.5 (v/v/v)water/acetonitrile/trifluoroacetic acid Flow Rate 1.0 mL/min Massdetection UV at 210 nm Radioactivity detection Ramona-D radioactivityflow detector Scintillator Tru-Count (Tru-Lab Supply Co.) Flow rate 5.0mL/min Cell volume 0.75 mL Retention time 7.7 min Result 98.7Radioactive Concentration by Scintillation Counting Method ScintillatorReady Safe (Beckman Instruments, Inc.) Instrument TM Analytic model 6881Efficiency Automated DPM calculation from quench curve Result 2.44mCi/mL Specific Activity by Mass Spectrometry Method CI-MS, NH₃ reagentgas Result 20.0 Ci/mmol ³H Distribution: Unlabeled 44% Single Label 43%Double Label 13% ³H NMR⁹ Method Instrument Brunker AM 400 ExperimentProton decoupled ³H NMR Proton non-decoupled ³H NMR Proton non-decoupled³H NMR Peak Referencing Solvent Peak of methanol @ 3.3 SolventMethanol-d₄ Result Tritium is incorporated exclusively on the carbonatoms ortho to aromatic hydroxyl group Analytical Summary Assay ResultRadiochemical purity 98.7% determined by HPLC Radioactivity concen- 2.44mCi/mL tration determined by scintillation counting specific activity20.0 Ci/mmol determined by mass spectrometry ³H NMR agrees with theproposed structure

Representative compounds of Formula (I), Examples 1 to 97, but for thecompound of example 2, which was not tested, and the compounds ofExamples 72, 83(d), 81(d), 81(e) have all demonstrated positiveinhibitory activity in this binding assay.

Prostoglandin endoperoxide synthase-2 (PGHS-2) assay:

The followiong assay describes a method for determining the inhibitoryeffects of compounds of Formula (I) on human PGHS-2 protein expressionin LPS stimulated human monocytes

Method:

Human peripheal blood monocytes were isolated from buffy coats bycentrifugation through Ficoll and Percoll gradients. Cells were seededat 2×10⁶/well in 24 well plates and allowed to adhere for 1 hour in RPMIsupplemented with 1% human AB serum, 20 mM L-glutamine,Penicillin-Streptomycin and 10 mM HEPES. Compounds were added at variousconcentrations and incubated at 37° C. for 10 minutes. LPS was added at50 ng/well (to induce enzyme expression) and incubated overnight at 37°C. The supernatant was removed and cells washed once in cold PBS. Thecells were lysed in 100 μl of cold lysis buffer(50 mM Tris/HCl pH 7.5,150 mM NaCl, 1% NP40, 0.5% sodium deoxycholate, 0.1% SDS, 300 μg/mlDNAse, 0.1% TRITON X-100, 1 mM PMSF, 1 mM leupeptin, 1 mM pepstatin).The lysate was centrifuged (10,000×g for 10 min. at 4° C.) to removedebris and the soluble fraction was subjected to SDS PAGE. analysis (12%gel). Protein separated on the gel were transferred onto nitrocellulosemembrane by electrophoretic means for 2 hours at 60 volts. The membranewas pretreated for one hour in PBS/0.1% Tween 20 with 5% non-fat drymilk. After washing 3 times in PBS/Tween buffer, the membrane wasincubated with a 1:2000 dilution of a monospecific antiserum to PGHS-2or a 1:1000 dilution of an antiserum to PGHs-1 in PBS/Tween with 1% BSAfor one hour with continuous shaking. The membrane was washed 3× inPBS/Tween and then incubated with a 1:3000 dilution of horseradishperoxidase conjugated donkey antiserum to rabbit Ig (Amersham) inPBS/Tween with 1% BSA for one hour with continuous shaking. The membranewas then washed 3× in PBS/Tween and the ECL immunodetection system(Amersham) was used to detect the level of expression of prostaglandinendoperoxide synthases-2.

RESULTS

The following compounds were tested and found to be active (inhibitedLPS induced PGHS-2 protein expression in rank order potency similar tothat for inhibiting cytokine production as noted in assays indicated):

1-[3-(4-Morpholinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole, arepresentative compound of Formula (I);

6-(4-Fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo[2,1-b]thiazole;

Dexamethasone

Several compounds were tested and found to be inactive (up to 10 uM):

2-(4-Methylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-(5H)-pyrrolo[1,2-a]imidazolerolipram; phenidone and NDGA

None of the compounds tested was found to inhibit PGHS-1 or cPLA₂protein levels in similar experiments.

SYNTHETIC EXAMPLES

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention. All temperatures aregiven in degrees centigrade, all solvents are highest available purityand all reactions run under anydrous conditions in an argon atmosphereunless otherwise indicated.

In the Examples, all temperatures are in degrees Centigrade (° C.). Massspectra were performed upon a VG Zab mass spectrometer using fast atombombardment, unless otherwise indicated. ¹H-NMR (hereinafter “NMR”)spectra were recorded at 250 MHz using a Bruker AM 250 or Am 400spectrometer. Multiplicities indicated are: s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat.indicates a saturated solution, eq indicates the proportion of a molarequivalent of reagent relative to the principal reactant.

Flash chromatography is run over Merck Silica gel 60 (230-400 mesh).

Example 11-[3-(4-Morpholinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

a) 4-fluorophenyl-tolylthiomethylformamide

A solution of p-fluorobenzaldehyde (13.1 milliliters (hereinafter mL),122 millimoles (hereinafter mmol) thiocresol (16.64 grams (hereinafterg), 122 mmol), formamide (15.0 mL, 445 mmol), and toluene (300 mL) werecombined and heated to toluene reflux with azeotropic removal of H₂O for18 h. The cooled reaction was diluted with EtOAc (500 mL) and washedwith satd aq Na₂CO₃(3×100 mL), satd aq NaCl (100 mL), dried (Na₂SO₄),and concentrated. The residue was triturated with petroleum ether,filtered and dried in vacuo to afford 28.50 g of the title compound as awhite solid (85%). melting point (hereinafter mp)=119-120°.

b) 4-fluorophenyl-tolylthiomethylisocyanide

The compound of example 1(a) (25 g, 91 mmol) in CH₂Cl₂ (300 mL) wascooled to −30° and with mechanical stirring POCl₃ (11 mL, 110 mmol) wasadded dropwise followed by the dropwise addition of Et₃N (45 mL, 320mmol) with the temperature maintained below −30°. Stirred at −30° for 30min and 5° for 2 h, diluted with CH₂Cl₂ (300 mL) and washed with 5% aqNa₂CO₃ (3×100 mL), dried (Na₂SO₄) and concentrated to 500 mL. Thissolution was filtered through a 12×16 cm cylinder of silica in a largesintered glass funnel with CH₂Cl₂ to afford 12.5 g (53%) of purifiedisonitrile as a light brown, waxy solid. IR (CH₂Cl₂) 2130 cm⁻¹.

c) Pyridine-4-carboxaldehyde [4-Morpholinylprop-3-yl]imine

Pyridine-4-carboxaldehyde (2.14 g, 20 mmoL), 4-(3-aminopropyl)morpholine(2.88 g, 20 mmol), toluene (50 mL) and MgSO₄ (2 g) were combined andstirred under argon for 18 h. The MgSO₄ was filtered off and thefiltrate was concentrated and the residue was reconcentrated from CH₂Cl₂to afford 4.52 g (97%) of the title compound as a yellow oil containingless than 5% of aldehyde based on ¹H NMR. ¹H NMR (CD₃Cl): d 8.69 (d,J=4.5 Hz, 2H), 8.28 (s, 1H), 7.58 (d, J=4.5 Hz, 2H), 3.8 (m, 6H), 2.44(m, 6H), 1.91 (m, 2H).

d) 1-[3-(4-Morpholinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

The compound of example 1(b) (1.41 g, 5.5 mmol), and the compound ofexample 1(c) (1.17 g, 5.0 mmol) and CH₂Cl₂ (10 mL) were cooled to 5° C.1.5.7-triazabicyclo[4.4.0]dec-5-ene, henceforth referred to as TBD,(0.71 g 5.0 mmol) was added and the reaction was kept at 5° C. for 16 h,diluted with EtOAc (80 mL) and washed with satd aq Na₂CO₃ (2×15 mL). TheEtOAc was extracted with 1 N HCl (3×15 mL), and the acid phases werewashed with EtOAc (2×25 mL), layered with EtOAc (25 mL) and made basicby the addition of solid K₂CO₃ til pH 8.0 and then 10% NaOH til pH 10.The phases were separated and the aq was extracted with additional EtOAc(3×25 mL). The extracts were dried (K₂CO₃) concentrated and the residuewas crystalized from acetone/hexane to afford 0.94 g (51%) of the titlecompound. mp=149-150°.

Example 2 1-(3-Chloropropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

a) Pyridine-4-carboxaldehyde (3-Chloropropyl)imine

To 3-chloropropylamine HCl (15.1 g, 0.120 moles (hereinafter mol)) andH₂O (100 mL) was added pyridine-4-carboxaldehyde (9.55 mL, 0.100 mol),then K₂CO₃ (8.28 g, 0.060 mol) then CH₂CL₂ (100 mL) and the mixture wasstirred for 40 min. The phases were separated and the aq phase wasextracted with additional CH₂Cl₂ (2×50 mL), dried (Na₂SO₄) andconcentrated to afford 17.1 g (94%) ¹H NMR (CD₃Cl): d 8.69 (d, J=4.5 Hz,2H, 8.32 (s, 1H), 8.28 (s, 1H), 7.58 (d, J=4.5 Hz, 2H), 3.71 (m, 2H),3.63 (t, J=6 Hz, 2H), 2.24 (t, J=6 Hz, 2H). The presence of 9% of thealdehyde was evident by ¹H NMR.

b) 1-(3-Chloropropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

The compound of example 1(b) (6.85 g, 26.6 mmol), the compound ofexample 2(a) (6.32g, 34.6 mmol), CH₂Cl₂ (70 mL), and TBD (4.07 g, 28.4mmol) were reacted by the procedure of example 1(d) to afford 3.19 g(38%). mp=139-140°.

Example 3 1-(3-Azidopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

To a solution of the compound of example 2(b) (250 milligram(hereinafter mg), 0.79 mmol) and DMF (5 mL) was added NaN₃ (256 mg, 3.95mmol) and NaI (12 mg, 0.08 mmol) and the mixture was heated to 90° tillthe reaction was completed based on tlc analysis (19:1 CH₂Cl₂/MeOH). Thecooled reaction was added to 5% aq Na₂CO₃ (20 mL) and extracted withEtOAc (3×25 mL). The combined extracts were washed with H₂O (3×25 mL)and flash chromatographed (2.2×10 cm column) with 0-1% MeOH in CH₂Cl₂ toafford 254 mg (100%) of the title compound as a white solid. mp=64-65°.

Example 4 1-(3-Aminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

The compound of example 3, described above (254 mg, 0.79 mmol), wasdissolved in THF (2 mL) an added dropwise to a 0° solution of 1 N LiAlH₄in THF (1.2 mL, 1.2 mmol), stirred at 0° for 15 min, EtOAc (4 mL) wascarefully added and the mixture was added to ice cold 10% NaOH (15 mL)and the product was extracted with EtOAc (4×25 mL), dried (K₂CO₃) andconcentrated to a waxy solid, (175 mg, 75%). mp=81-82°.

Example 51-(3-Methylsulfonamidopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

To the compound of Example 4, described above (79 mg, 0.26 mmol) inCH₂Cl₂ (0.5 mL) was added Et₃N (72 uL, 0.52 mmol), and thenmethanesulfonyl chloride (25 uL, 0.31 mmol). The reaction exothermed toCH₂Cl₂ reflux briefly. The reaction was over within 1 min based on tlc(19:1 CH₂Cl₂/MeOH) and was poured into 10% NaOH (5 mL) and extractedwith EtOAc (3×20 mL). The extracts were washed with H₂O (10 mL) and satdaq Nacl (10 mL), dried (Na₂SO₄), concentrated and flash chromatographed(1×10 cm silica) with 0-8% MeOH in CH₂Cl₂ to afford 63 mg (65%).mp=186-187°.

Example 61-[3-(N-Phenylmethyl)aminopropyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 3 above, except using benzylamine asthe nucleophile and purification of the crude product by triturationwith hot hexane, the title compound was prepared as a white solid (32%yield). mp=125-126°.

Example 71-[3-(N-Phenylmethyl-N-methyl)aminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 3 except using N-benzylmethylamine asthe nucleophile and purification of the crude product by triturationwith hot hexane, the title compound was prepared as a white solid (42%yield). mp=90-91°.

Example 81-[3-(1-Pyrrolidinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 3 except using pyrrolidine as thenucleophile and purification of the crude product by trituration withhot hexane, the title compound was prepared as a white solid (35%yield). mp=105-107°.

Example 91-(3-Diethylaminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 3 except using diethylamine as thenucleophile and isolation of the product by extraction with diethylether, the title compound was prepared as a white solid (21% yield).mp=94-95°.

Example 101-[3-(1-Piperidinyl)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 3 except using piperidine as thenucleophile and purification of the crude product by trituration withhot hexane, the title compound was prepared as a white solid (63%yield). mp=105-108°.

Example 111-[3-(Methylthio)propyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 3 except using sodium thiomethane asthe nucleophile and omitting the sodium iodide followed by purificationof the crude product by trituration with hot hexane, the title compoundwas prepared as a white solid (50% yield). mp=85-86°.

Example 121-[2-(4-Morpholinyl)ethyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

a) Pyridine-4-carboxaldehyde-[2-(4-Morpholinyl)ethyl]imine

Following the procedure of example 1(c) except using4-(2-aminoethyl)morpholine as the amine, the title compound was preparedas a light yellow oil (100%) containing less than 10% of aldehyde basedon ¹H NMR. ¹H NMR (CD₃Cl): d 8.68 (d, J=6 Hz, 2H), 8.28 (s, 1H), 7.58(d, J=6 Hz, 2H), 3.82 (m, 2H), 3.72 (m, 4H), 2.72 (m, 2H), 2.55 (m, 4H).

b) 1-[2-(4-Morpholinyl)ethyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1(d) except using the compound ofexample 20(a) as the imine, afforded the title compound as a white solid(21%). mp=114-115°.

Example 131-[3-(4-Morpholinyl)propyl]-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole

a) N-[3-methylthiophenyl-(tolylthio)methyl]formamide

Following the procedure of example 1(a) except usingm-methylthiobenzaldehyde as the aldehyde, the title compound wasprepared as a white solid (73%). mp=103-104°.

b) 3-methylthiophenyl-(tolylthio)methylisocyanide

Following the procedure of example 1(b) except using the compound of theprevious step as the formamide, the title compound was prepared as alight brown oil (77%). IR (CH₂Cl₂) 2120 cm⁻¹.

c)1-[3-(4-Morpholinyl)propyl]-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the isonitrile, afforded the title compound as a whitesolid (31%). mp=105-106°.

Example 141-[3-(4-Morpholinyl)propyl]-4-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole

The compound of example 13(c) (200 mg, 0.49 mmol) was dissolved in HOAc(4 mL). K₂S₂O₈ (151 mg, 0.56 mmol) dissolved in H₂O was added and thesolution was stirred for 16 h, poured into 10% aq NaOH (50 mL) (theresulting solution was >pH 10) and extracted with EtOAc (3×25 mL). Theextracts were dried (K₂CO₃), concentrated and the residual oilcrystalized from acetone/hexane to afford 87 mg (42%) of a white solid.mp=117-118°.

Example 151-[3-(N-methyl-N-benzyl)aminopropyl]-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole

a) Pyridine-4-carboxaldehyde 3-(N-methyl-N-benzylaminopropyl)imine

Following the procedure of example 1(c) except using3(-N-Methyl-N-benzylamino)propylamine as the amine (Ueda,T.;Ishizaki,K.; Chem. Pharm. Bull. 1967, 15, 228-237.), the title compoundwas obtained as a light yellow oil (100%) containing less than 10% ofaldehyde based on ¹H NMR. ¹H NMR (CD₃Cl): d 8.65 (d, J=7 Hz, 2H), 8.21(s, 1H), 7.54 (d, J=4.5 Hz, 2H), 7.52 (m, 5H), 3.69 (t, J=11 Hz, 2H),3.48(s, 2H), 2.44 (t, J=11 Hz, 2H), 2.18 (s, 3H), 1.91 (m, 2H).

b)1-[3-(N-methyl-N-benzyl)aminopropyyl]-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1(d) except using the compound ofexample 13(b) as the isonitrile, and the compound prepared in theprevious step as the imine afforded the title compound as a white solid(36%). mp=87-88°.

Example 161-[3-(N-methyl-N-benzyl)aminopropyl]-4-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 14 except using the compound ofexample 15(b) as the sulfide afforded the title compound as a whitesolid (97%). mp=84-85°.

Example 171-[4-(Methylthio)phenyl]-4-(4-fluorophenvyl-5-(4-pyridyl)imidazole

a) Pyridine-4-carboxaldehdye (4-methylthiophenyl)imine

Following the procedure of example 1(c) except using4-(methylthio)aniline as the amine afforded (100%) of a light yellow oilwith no detectable amount of aldehyde based on ¹H NMR. ¹H NMR (CD₃Cl): d8.75 (d, J=6 Hz, 2H), 8.47 (s, 1H), 7.74 (d, J=6 Hz, 2H), 7.30 (d, J=8Hz, 2H), 7.22 (d, J=8 Hz, 2H), 2.52(s, 3H).

b) 1-[4-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound as a white solid(27%). mp=172-173°.

Example 181-[4-(Methylsulfinyl)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 14 except using the compound ofexample 17(b) as the sulfide afforded the title compound as a whitesolid (67%). mp=202-203°.

Example 191-[3-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

a) Pyridine-4-carboxaldehdye (3-methylthiophenyl)imine

Following the procedure of example 1(c) except using3-(methylthio)aniline as the amine afforded (98%) of a light yellow oilwith ca 2.5% of aldehyde based on ¹H NMR. ¹H NMR (CD₃Cl): d 8.76 (d, J=6Hz, 2H), 8.44 (s, 1H), 7.74 (d, J=6 Hz, 2H), 7.30 (d, J=8 Hz, 2H),7.34-6.98 (m, 4H), 2.52(s, 3H).

b) 1-[3-(methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1 (d) except using the compound ofthe previous step as the imine afforded the title compound as a whitesolid (42%). mp=155-156°.

Example 201-[3-(Methylsulfinyl)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 14 except using the compound ofexample 19(b) as the sulfide afforded the title compound as a whitesolid (67%). mp=233-234°.

Example 211-[2-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

a) Pyridine-4-carboxaldehdye (2-methylthiophenyl)imine

Following the procedure of example 1(c) except using2-(methylthio)aniline as the amine afforded (98%) of a light yellow oilwith ca 8% of aldehyde based on ¹H NMR. ¹H NMR (CD₃Cl): d 8.75 (d, J=6Hz, 2H), 8.41 (s, 1H), 7.79 (d, J=6 Hz, 2H), 7.36-7.00 (m, 4H), 2.47(s,3H).

b) 1-[2-(methylthio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine and purification by flash chromatography with0-1% MeOH in CH₂Cl₂ afforded the title compound as a non-crystallinewhite foam (53%). mp=59-60°.

Example 221-[2-(Methylsulfinyl)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 14 except using the compound ofexample 21(b) as the sulfide, and purification by flash chromatographywith 0-4% MeOH in CH₂Cl₂ afforded the title compound as anon-crystalline white foam (52%). mp=60-165°. (The ill defined mp isprobably the result of a mixture of conformational isomers which isclearly indicated in the ¹H and ¹³C NMR spectra of this compound.)

Example 23 1-(3-Chloropropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

(See also Example 2 above for alternative method of preparation)

a) 4-Fluorophenyl-tosylmethylformamide

To a solution of toluene sulphinic acid sodium salt hydrate (120 g) inwater (750 ml) was added concentrated sulphuric acid (16 ml).Dichloromethane (500 ml) was added and the organic and aqueous layerswere separated; the aqueous layers being extracted with dichloromethane(2×200 ml). The combined organic extracts were dried (Na₂SO₄) andevaporated to dryness to yield the solid sulphinic acid (71.79 g, 0.46mole). This was added to p-fluorobenzaldehyde (57.04 g, 0.46 mole) andformamide (62.1 g, 1.38 mole) and the resulting mixture was stirred withcamphor-10-sulphonic acid (21.3 g, 0.092 mole) at 60-65°, under nitrogenfor 22 hours. A solution of sodium bicarbonate (33.6 g, 0.40 mole) inwater (400 ml) was added to the ice-cooled solid product which wasbroken up and stirred for 30 minutes. The crude product was collectedand washed with acetone (220 ml) and then ether (3×220 ml) and dried toyield the desired product, 91.5 g, 64.8%.

b) 4-Fluorophenyl-tosylmethylisocyanide

To a suspension of the compound of the previous step (3.22 g, 10.5mmole) in dimethoxyethane (21 ml) stirring at −10° was added phosphorusoxychloride (2.36 ml, 25.3 mmole) dropwise over 5 minutes. Triethylamine(7.35 ml, 52.5 mmole) was then added dropwise over 10 minutes and thereaction mixture was poured into saturated sodium bicarbonate solution(100 ml) and the oily product was extracted into dichloromethane (2×30ml). The organic extracts were evaporated to yield a black oil (3.51 g)which was eluted from Grade III basic alumina (60 g) usingdichloromethane. The combined product fractions were evaporated andether added to crystallize the desired product, 1.735 g, 57%.

c) 1-(3-Chloropropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-imidazole

To a solution of the compound of the previous step (1.183 g, 4.09 mmol)and the compound of example 2(a) (1.122 g, 6.15 mmole) indimethoxyethane (15 ml) at ambient temperature was added dropwise over10 minutes a solution of DBU (0.67 ml, 4.51 mmole) in dimethoxyethane(10 ml). The reaction mixture was stirred at ambient temperature for 1½hours and then evaporated to leave an oil which was eluted from GradeIII basic alumina (100 g) to yield the desired product, 1.096 g, 85%.

Example 241-[4-(4-Morpholinyl)butyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

a) 4-(4-Morpholino)butyl-1-pthalimide

4-Bromobutyl-1-pthalimide (5.0 g, 17.7 mmol) and morpholine (20 mL) werecombined and stirred for 3 h, diluted with Et₂O (200 mL), and filtered.The solid was washed with more Et₂O and the combined filtrates wereextracted with 3 N HCl (3×25 mL). The combined acid phases were washedwith Et₂O (3×50 mL), layered with EtOAc and made basic by the additionof solid K₂CO₃ til the foaming stopped and then 10% aq NaOH was addedtil the pH was >10. Extraction with EtOAc (3×100 mL), drying, (K₂CO₃),concentration and flash filtration 1 L silica wash first with 0-4% MeOHin CH₂Cl₂ and then elute product with 4% MeOH and 1% E_(t3)N in CH₂Cl₂to afford 5.52 g (54%) of the title compound as a white solid.

b) 4-(4-Morpholino)butylamine

The compound of example 24 (a) (1.0 g, 3.47 mmol), hydrazine monohydrate(190 μl, 3.82 mmol) and CH₃OH (20 mL) were combined and stirred at 23°overnight. The CH₃OH was removed in vacuo and the resudue wasconcentrated to dryness from EtOH. The residue was combined with 2N HCl(20 mL) and stirred for 2 h, filtered and the solid was washed with H₂O.The combined filtrates were concentrated in vacuo and reconcentratedfrom EtOH twice to give a white foam which was dissolved in 3:1CH₂Cl₂/CH₃OH, and stirred with solid K₂CO₃ for 5 min and filtered. Thefiltrate was concentrated to afford 0.535 g (80%) of a brown oil. ¹H NMR(CD₃Cl): 3.7-3.2 (m, 6H), 2.7-2.2 (m, 6), 1.6-1.3 (m, 6H).

c) Pyridine-4-carboxaldehyde [4-(4-morpholinyl)butyl]imine

Following the procedure of example 1 (c) except using the compound ofexample 24(b) as the amine the title compound was prepared as a lightyellow oil (100%) containing 30% of aldehyde based on ¹H NMR. ¹H NMR(CD₃Cl): 8.60 (d, J=6 Hz, 2H), 8.19 (s, 1H), 7.51 (d, J=6 Hz, 2H),3.7-3.2 (m, 6H), 2.5-2.2 (m, 6), 1.7-1.4 (m, 4H).

d) 1-[4-(4-Morpholinyl)butyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1(d) except using the compound ofexample 24(c) as the imine afforded the title compound (38%).mp=103-104°.

Example 25 1-Cyclopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

a) Pyridine-4-carboxaldehyde cyclopropylimine

Following the procedure of example 1(c) except using a 100% excess ofthe volatile cyclopropylamine the title compound was prepared as a lightyellow oil (100%). ¹H NMR (CD₃Cl): 8.65 (d, J=6 Hz, 2H), 8.40 (s, 1H),7.51 (d, J=6 Hz, 2H), 3.07 (m, 1H), 1.01 (m, 4H)

b) 1-Cyclopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

The compound of the previous step (20 mmol), the compound of example1(b) (5.65 g, 22 mmol), and CH₂Cl₂ (20 mL) were cooled to 0° and TBD(2.84 g, 20 mmol) was added. Stirred at 5° for 2 h, 23° for 48 h andrefluxed for 4 h. The crude reaction was flash filtered through asintered glass funnel filled with silica (1 L of silica) eluting with0-4% CH₃OH in CH₂Cl₂. Crystals from hexane/acetone to afford 839 mg(15%) mp=129.0-129.5°.

Example 26 1-Isopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

a) Pyridine-4-carboxaldehyde isopropylimine

Following the procedure of example 1(c) except using isopropylamine asthe amine the title compound was prepared as a light yellow oil (100%).¹H NMR (CD₃Cl): 8.67 (d, J=4.4 Hz, 2H), 8.27 (s, 1H), 7.59 (d, J=4.43Hz, 2H), 3.59 (m, 1H), 1.27 (d, J=6.3 Hz, 6H).

b) 1-Isopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1(d) and substituting the imine ofthe previous step the compound was prepared using a modified work up offlash filtration of the crude reaction through silica (0-4% CH₃OH inCH₂Cl₂). Two crystallizations from hexane/acetone afforded the titlecompound as tan needles (30%). mp=179.0-179.5.

Example 27 1-Cyclopropylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

a) Pyridine-4-carboxaldehyde Cyclopropylmethylimine

Following the procedure of example 1(c) except usingcyclopropylmethylamine as the amine the title compound was prepared as alight yellow oil (100%). ¹H NMR (CD₃Cl): 8.69 (d, J=4.5 Hz, 2H), 8.27(s, 1H), 7.61 (d, J=4.5 Hz, 2H), 3.55 (d, J=6.7 Hz, 2H), 1.15 (m, 1H),0.57 (m, 2H), 0.27 (m, 2H).

b) 1-Cyclopropylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1(d) substituting the imine of theprevious step the compound was prepared using a modified work up offlash filtration of the crude reaction through silica (0-4% CH₃OH inCH₂Cl₂). Crystallization from hexane/acetone afforded the title compoundas white flakes (62%). mp=162.0-162.5.

Example 28 1-tert-Butyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

a) Pyridine-4-carboxaldehyde tert-butylimine

Following the procedure of example 1(c) except using tert-butylamine asthe amine the title compound was prepared as a light yellow oil (100%).¹H NMR (CD₃Cl): 8.67 (d, J=4.4 Hz, 2H), 8.22 (s, 1H), 7.61 (d, J=4.4 Hz,2H), 1.30 (s, 9H).

b) 1-tert-Butyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1(d) substituting the imine of theprevious step the compound was prepared using a modified work up offlash filtration of the crude reaction through silica (0-4% CH₃OH inCH₂Cl₂) to afford the title compound as tan powder (16%). mp=199.0-200.0

Example 291-(2,2-Diethoxyethyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

a) Pyridine-4-carboxaldehyde 2,2-diethoxyethylimine

Following the procedure of example 1(c) except using2,2-diethoxyethylamine as the amine the title compound was prepared as alight yellow oil (100%). ¹H NMR (CD₃Cl): 8.69 (d, J=4.4 Hz, 2H), 8.28(s, 1H), 7.60 (d, J=4.4 Hz, 2H), 4.82 (t, J=5.1 Hz, 1HO, 3.82 (d, J=5.1Hz, 1H), 3.72 (m, 2H), 3.57 (m, 2H), 1.21 (t, J=7.3 Hz, 6H).

b) 1-(2,2-Diethoxyethyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1(d) substituting the imine of theprevious step, the compound was prepared using a modified work up offlash filtration of the crude reaction through silica (0-4% CH₃OH inCH₂Cl₂), followed by a flash chromatography through silica with 25-100%EtOAc in hexane) and trituration of the resulting gum with hexaneafforded the title compound as a white powder (47%). mp=69.5-70.0.

Example 30 1-Formylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

The product of example 29(b) (400 mg, 1.13 mmol), H₂O (10 mL), acetone(10 mL) and concd H₂SO₄ (1 mL) were combined and refluxed for 24 h. Mostof the acetone was removed in vacuo and the residue was combined with 5%aq Na₂CO₃ and extracted with EtOAc, dried (Na₂SO₄), concentrated andcrystallyzed from acetone to afford the title compound as a white powder(47%). mp=118.5-119.0.

Example 311-Hydroxyiminylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

The product of example 30 (317 mg, 1.13 mmol), hydroxylaminehydrochloride (317 mg), pyridine (317 μL), and EtOH (3.8 mL) werecombined and refluxed for 3 h, poured into 5% aq Na₂CO₃, and extractedwith EtOAc, dried (Na₂SO₄) and flash filtered in 0-4% MeOH in CH₂Cl₂ toafford 261 mg (78%) of the title compound as a white powder.mp=184.0-185.0.

Example 32 1-Cyanomethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

The product of example 31 (250 mg, 0.84 mmol), and CuSO₄ were combinedand refluxed for 2 h. The cooled reaction was flash filtered in 0-4%MeOH in CH₂Cl₂ to afford 129 mg (55%) of the title compound as a whitepowder. mp=132.0-133.0.

Example 331-[3-(4-Morpholinyl)propyl)-4-(4-fluorophenyl)-5-(2-methylpyrid-4-yl)imidazole

a) 4-Formyl-2-methylpyridine

4-Cyano-2-methylpyridine was prepared from 2,6-lutidine asccording tothe literature procedure (Yamanaka,H.; Abe,H.; Sakamoto,T.; Hidetoshi,Hiranuma,H.; Kamata,A. Chem. Pharm. Bull. 25(7), 1821-1826.). A solutionof 4-Cyano-2-methylpyridine (0.367 g, 3.11 mmoL) and toluene (3.5 mL)was cooled to −78° and 1 M DIBAL in hexanes (3.6 mL, 3.6 mmoL) was addeddropwise via syringe pump (T<−65°). The reaction was warmed to 5° andstirred for 5 min, recooled to −78° and CH₃OH (3.5 mL) was added(T<−40°), warmed to 5° and stirred for 5 min and then 25% aq Rochelle'ssalt was added, stirred for 3 min and then acidified to <pH 1.0 with 10%aq H₂SO₄. The aqueous was made basic by the addition of solid K₂CO₃ andextracted with EtOAc. The extracts were dried (Na₂SO₄) concentrated andfiltered through silica (2% MeOH in CH₂Cl₂) to afford 253 mg (84%) ofaldehyde. H¹ NMR (CD₃Cl): d 10.05 (s, 1H), 8.74 (d, J=7 Hz, 1H), 7.51(s, 1H), 7.30 (d, J=7 Hz, 1H), 2.68 (s, 3H).

b) Pyridine-4-carboxaldehyde [3-(4-morpholinyl)propyl]imine

The product of the previous step and 4-(3-aminopropyl)morpholine werereacted by the procedure of example 1(c) to afford the title compound asa yellow oil containing no aldehyde based on ¹H NMR. ¹H NMR (CD₃Cl): d8.57 (d, J=5.0 Hz, 1H), 8.25 (s, 1H), 7.46 (s, 1H); 7.36 (d, J=5.0 Hz,1H), 3.71 (m, 6H), 2.60 (s, 1H); 2.35 (m, 6H), 1.90 (m, 2H).

c)1-[3-(4-Morpholinyl)propyl)-4-(4-fluorophenyl)-5-(2-methylpyrid-4-yl)imidazole

The compound of the previous step, and the compound of example 1(b) werereacted by the procedure of example 1(d) to afford the title compound asa white solid [51% from 33 (a)]. mp=116-117°.

Example 344-(4-Fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(2-chloropyridin-4-yl)imidazole

a) 2-Chloropyridine-4-carboxaldehyde [3-(4-morpholinyl)propyl]imine

2-Chloropyridine-4-carboxaldehyde was prepared as described in thepatent literature (WPI Acc. No. 88-258820/37) whose disclosure isincorporated by reference in its entirety herein. This aldehyde wasreacted with 4-(3-aminopropyl)morpholine by the procedure of example1(c) to afford the title compound as a yellow oil. ¹H NMR (CD₃Cl): δ8.45 (d, J=5.1 Hz, 1H), 8.24 (s, 1H), 7.63 (s, 1H); 7.51 (d, J=5.1 Hz,1H), 3.72 (m, 6H), 2.44 (m, 6H), 1.91 (m, 2H).

b)4-(4-Fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(2-chloro-4-pyridinyl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound as a white solid(93%). mp=97.0-97.5°.

Example 354-(4-Fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(2-amino-4-pyridinyl)imidazole

a)4-(4-Fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(2-hydrazinyl-4-pyridinyl)imidazole

The compound of example 34(b) (872 mg, 2.18 mmoL) and 98% hydrazinehydrate (9 mL) was heated to 115° (bath temp) for 20 h, cooled to 23°combined with H₂O (20 mL) and extracted with EtOAc (3×25 mL). Thecombined extracts were washed with H₂O (2×20 mL) and dried (Na₂SO₄).Flash chromatography with 0-8% CH₃OH in CH₂Cl₂ afforded 547 mg (63%) thetitle compound as a white solid.

b)4-(4-Fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(2-amino-4-pyridinyl)imidazole

The compound of the previous step (100 mg, 0.25 mmoL), absolute EtOH (15mL) and Raney Ni (0.4 mL) were shaken under H₂ (45 psi) for 4 h. Flashchromatography with 0-8% CH₃OH in CH₂Cl₂ afforded 34 mg (37%) the titlecompound as a white solid. mp=186-187°.

Example 361-(4-Carboxymethyl)propyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

a) Pyridine-4-carboxaldehyde (4-carboxymethylbutyl)imine

Pyridine-4-carboxaldehyde was reacted with methyl-4-aminobutyrate by theprocedure of example 1(c) to afford the title compound as a yellow oil.¹H NMR (CD₃Cl): δ 8.69 (d, J=5.8 Hz, 2H), 8.27 (s, 1H); 7.56 (d, J=5.8Hz, 2H), 3.70 (m, 2H); 2.31 (t, J=8.0 Hz, 2H), 2.08 (m, 2H).

b) 1-(4-Carboxymethyl)propyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound as a white solid(35%). mp=69.0-70.0°.

Example 37 1-(4-Carboxypropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

The compound of example 36 (100 mg, 0.29 mmol), CH₃OH (3 mL), and THF(1.5 mL) were combined and the resulting soln was treated with a soln ofLiOH (62 mg, 1.5 mmol) in H₂O (1.5 mL) and the resulting soln wasstirred for 4 h. Removal of the volatile compounents in vacuo,redisolving in H₂O and chromatography through HP-20 with H₂O til theeluates were neutral and then with 25% aq MeOH afforded the titlecompound as the lithium salt; 65 mg (68%). ES (+) MS m/e=326 (MH⁺).

Example 381-(3-Carboxymethyl)ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

a) Pyridine-4-carboxaldehyde (3-carboxymethyl)ethyl imine

Pyridine-4-carboxaldehyde was reacted with β-alanine methyl ester by theprocedure of example 1(c) to afford the title compound as a yellow oil.¹H NMR (CD₃Cl): δ 8.68 (d, J=4.5 Hz, 2H), 8.33 (s, 1H); 7.57 (d, J=4.5Hz, 2H), 3.93 (t, J=6.7 Hz, 2H); 3.68 (s, 3H), 2.76 (t, J=6.7 Hz, 2H),

b) 1-(3-Carboxymethyl)ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazoleSB-219302

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound as a white solid(40% from the amine). mp=119.0-120.0°.

Example 39 1-(3-Carboxy)ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

The compound of example 38(b) was hydrolysed by the procedure of example37 to afford the title compound as the lithium salt; (71%). ES (+) MSm/e=312 (MH⁺).

Example 401-(1-Benzylpiperidin-4-yl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

a) Pyridine-4-carboxaldehyde (1-benzylpiperidin-4-yl)imine

Pyridine-4-carboxaldehyde was reacted with 4-amino-N-benzylpiperidine bythe procedure of example 1(c) to afford the title compound as a yellowoil.

b) 1-(1-Benzylpiperidin-4-yl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1(d) except using the compound ofexample the previous step as the imine afforded the title compound as awhite solid (9% from the amine). ES (+) MS m/e=413 (MH⁺).

Example 415-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-[3-(4-Morpholinyl)propyl]imidazole

a) 2-Aminopyrimidine-4-carboxaldehyde dimethyl acetal

Dimethylformamide dimethyl acetal (55 mL, 0.41 mol), and pyruvicaldehyde dimethyl acetal (50 mL, 0.41 mol) were combined and heated to100° for 18 h. Methanol was removed in vacuo to afford an oil.

A solution of NaOH (18 g, 0.45 mol) in H₂O (50 mL) was added toguanidine HCl (43 g, 0.45 mol) in H₂O (100 mL), and the resultingsolution was added to the above described oil. The resulting mixture wasstirred at 23° for 48 h. Filtration afforded 25 g (50%) of the titlecompound.

b) 2-Aminopyrimidine-4-carboxaldehyde

The compund of the previous step (1.69 g, 10 mmol) and 3N HCl (7.3 mL,22 mmol) were combined and heated to 48° for 14 h, cooled, layered withEtOAc (50 mL) and neutralized by the addition of NaHCO₃ (2.1 g, 25 mmol)in small portions. The aq phase was extracted with EtOAc (5×50 mL) andthe extracts were dried (Na₂SO₄)and concentrated to afford 0.793 g (64%)of the title compound.

c) 2-Aminopyrimidine-4-carboxaldehyde [3-(4-Morpholinyl)propyl]imine

The compound of the previous step and 4-(3-aminopropyl)morpholine werereacted by the procedure of example 1(c) to afford the title compound asa yellow oil.

d)5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-[3-(4-Morpholinyl)propyl]imidazoleSB 216385

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound as a white solid.¹H NMR (CD₃Cl) δ 8.15(d, J=5.4 Hz, 1H), 7.62(s, 1H), 7.46 (dd, 2H),7.00(t, J=8.6 Hz, 2H), 6.50(d, J=5.4 Hz, 1H), 5.09(brd.s, 2H), 4.34(t,J=7.0 Hz, 2H), 3.69(m, 4H), 2.35(brd.s, 4H), 2.24(t, J=4.6 Hz, 2H),1.84(m, 2H).

Example 425-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(1-benzylpiperidin-4-yl)imidazole

a) 2-Aminopyrimidine-4-carboxaldehyde (1-benzylpiperidin-4-yl)imine

2-Aminopyrimidine-4-carboxaldehyde and 4-aminobenzylpiperidine werereacted by the procedure of example 1(c) to afford the title compound asa yellow oil.

b)5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(1-benzylpiperidin-4-yl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound as a white solid(31% from the amine). mp=227-229° (dec).

Example 435-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(2-propyl)imidazole

a) 2-Aminopyrimidine-4-carboxaldehyde (2-propyl)imine

2-Aminopyrimidine-4-carboxaldehyde and 2-propyl amine were reacted bythe procedure of example 1(c) to afford the title compound as a yellowoil.

b) 5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(2-propyl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound as a white solid(32% from the 2-aminopyrimidine aldehyde). mp=201-202°.

Example 445-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(cyclopropylmethyl)imidazole

a) 2-Aminopyrimidine-4-carboxaldehyde (cyclopropylmethyl)imine

2-Aminopyrimidine-4-carboxaldehyde and 2-cyclopropylmethyl amine werereacted by the procedure of example 1(c) to afford the title compound asa yellow oil.

b)5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(cyclopropylmethyl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound as a white solid(38% from the 2-aminopyrimidine aldehyde). mp=187-188°.

Example 455-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(1-carboxyethyl-4-piperidinyl)imidazole

a) 2-Aminopyrimidine-4-carboxaldehyde(1-carboxyethyl-4-piperidinyl)imine

2-Aminopyrimidine-4-carboxaldehyde and 1-carboxyethyl-4-aminopiperidinewere reacted by the procedure of example 1(c) to afford the titlecompound as a yellow oil.

b)5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(1-carboxyethyl-4-piperidinyl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound as a white solid(26% from the 2-aminopyrimidine aldehyde). mp=216-218° (dec).

Example 465-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole

a) 2-Aminopyrimidine-4-carboxaldehyde(1-t-butoxycarbonyl-4-aminopiperidinyl)imine

2-Aminopyrimidine-4-carboxaldehyde prepared in Example 41 and1-t-butoxycarbonyl-4-aminopiperidine (Mach R. H., et.al., J. Med. Chem.36, p3707-3719, 1993) were reacted by the procedure of example 1(c) toafford the title compound as a yellow oil.

b)5-[4-(2-Amino)pyrimidinyl]-4-(4-fluorophenyl)-1-(1-t-butoxycarbonylpiperidin-4-yl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound as a white solid(27% from the 2-aminopyrimidine aldehyde).

c)5-[4-(2-Amino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole

The compound of the previous step was combined with 4N HCl in dioxane (5mL), stirred 10 min, diluted wilth EtOAc and the liquid phase wasdecanted. The solid was twice washed with Et₂O (25 mL) and the liquidphase was decanted. Further trituration with EtOH (abs) and then Et₂Oand drying in vacuo at 50° for 16 h afforded the title compound as thetrihydrochloride (41%). mp=265-275 (dec).

Example 47 1-Methyl-4-phenyl-5-(4-pyridyl)imidazole

Following the procedure of example 48(b) except using benzonitrile thetitle compound as a white solid. mp=161-162°.

Example 48 1-Methyl-4-[3-(chlorophenyl)]-5-[4-pyridinyl]imidazole

a) N-(4-Pyridinylmethyl)-N′-methylformamide

To a stirring, argon-purged solution of 4-picolyl chloride-HCl (15 g,91.4 mmol) and N-methylformamide (53.4 ml, 914 mmol) in 300 ml of THF atroom temperature was added portionwise over a 20 minute period asuspension of 80% NaH (5.48 g, 183 mmol). The reaction was quenched 18 hlater by the addition of ice, partitioned between methylene chloride andwater, washed with water and brine, dried over MgSO₄, and evaporated todryness to afford a dark oil. Flash chromatography on silica gelprovided 10.5 g (76%) of the titled compounds a pale yellow oil. TLC;silica gel (9:1 CHCl/MeOH) Rf=0.54.

b) 1-Methyl-4-[3-(chlorophenyl)]-5-[4-pyridinyl]imidazole

To a stirred, argon-covered, −78° solution of lithium diisopropylamide(hereinafter LDA), (prepared from 11.2 ml of diisopropylamine in 150 mlof tetrahydrofuran (hereinafter THF) by the addition of 31.9 ml of 2.5Mn-BuLi in hexanes) was added dropwise the product of the previousreaction (10 g, 66.5 mmol) in 100 mL of THF. Stirring of the resultantreddish-brown solution was continued at −78° for 40 min at which point3-chlorobenzonitrile (18.3 g, 133 mmol) in 100 mL THF was added dropwiseover 20 min. The reaction was allowed to warm to room temperature,stirred for 1 h and heated to reflux for 12 h. The reaction was cooledand worked up in a manner similar to the previous reaction. Flashchromatography on silica gel provided 2.15 g of an oil which wascrystallized by dissolution with heating in 10 mL of ethyl acetate.Following crystallization, the solid was collected, washed, and dried(0.4 mm Hg) to afford 1.43 g (8%) of the titled compound as a light tansolid. mp=119-121°.

Example 49 1-Methyl-4-(3-methylthiophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 48(b) except using the compound ofexample 13(b) as the aryl nitrile the title compound was obtained as awhite solid. ES (+) MS m/e=281 (MH⁺).

Example 50 1-Methyl-4-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 14 except using the compound ofexample 49 as the sulfide the title compound was obtained as a whitesolid. ES (+) MS m/e=297 (MH⁺).

Example 51(+/−)-4-(4-Fluorophenyl)-1-[3-(methylsulfinyl)propyl]-5-(4-pyridinyl)imidazole

Following the procedure of example 14 except using the compound fromexample 11 as the sulfide and quenching with saturated aq NH₄OH affordedthe title compound as a white solid (0.87 g, 80%). mp=122-123°.

Example 524-(4-Fluorophenyl)-1-[(3-methylsulfonyl)propyl]-5-(4-pyridinyl)imidazole

The compound of Example 51 (0.5087 g, 1.48 mmol) was dissolved inmethanol (8 ml) and cooled to 0° C. The addition of trifluoroacetic acid(0.12 ml) was followed by the dropwise addition ofmeta-chloroperoxybenzoic acid (0.23 g, 2.22 mmol) dissolved in CH₂Cl₂(10 ml). After stirring for 1 h the solvents were evaporated. Theresidue was partitioned between H₂O and EtOAc and the aqueous phase wasmade basic by the addition of 2N NaOH. The organic phase was separated,dried (MgSO₄) and concentrated and the residue was pruified by flashchromatography (silica gel, 5% MeOH/CH₂Cl₂) to afford the title compound(0.37 g, 69%). mp=146-147°.

Example 531-(3-Phenoxypropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole

To a solution of the compound from example 2(b) (0.22 g, 0.70 mmol) inacetonitrile (10 ml) was added K₂CO₃ (0.19 g, 1.40 mmol) and phenol(0.10 g, 1.05 mmol). After stirring at 70° C. for 24 h the reaction wasdiluted with H₂O. The organic phase was separated and concentrated andthe residue was purified by flash chromatography (silica gel, 5%MeOH/CH₂Cl₂) followed by recrystalization in hexane to afford the titlecompound (0.02 g, 8%) as a white solid. mp=95-96°.

Example 541-[3-(Phenylthio)propyl]-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole

Following the procedure for example 3 except using thiophenol as thenucleophile, adding 2.2 eq K₂CO₃ and omitting the NaI. The cooledreaction was diluted with 10% NaOH and the product was extracted withether. Flash chromatography was followed by recrystalization from hexaneto afford the title compound (0.13 g, 53%) as white needles. mp=98-99°.

Example 551-[3-(4-Morpholinyl)propyl]-4-(4-fluorophenyl)-5-(4-quinolyl)imidazole

a) Quinoyl-4-carboxaldehyde [3-(4-Morpholinyl)propyl]imine

Quinoyl-4-carboxaldehyde and 4-(3-aminopropyl)morpholine were reacted bythe procedure of example 1(c) to afford the title compound as a yellowoil.

b)1-[3-(4-Morpholinyl)propyl]-4-(4-fluorophenyl)-5-(4-quinolyl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound as a white solid(48% from the amine). mp=139.5-140.0.

Example 56(+/−)-1-(3-Phenylsulfinylpropyl-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole

Following the procedure of example 14 except using the compound fromexample 54 as the sulfide and quenching with saturated aq NH₄₀H affordedthe title compound as a white solid. mp=146.5-148°.

Example 571-(3-Ethoxypropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole

To a solution of the compound of example 2(b) (0.40 g, 1.26 mmol) inethanol 25 ml) was added sodium ethoxide (0.8 ml, 21 wt % in ethanol).After refluxing 16 h the mixture was cooled, diluted with H₂O andextracted with EtOAc. Concentration of the solvent and purification byflash chromatography (silica gel, 5% MeOH/CH₂Cl₂) afforded the titlecompound (0.05 g, 12%). mp=85-86°.

Example 581-(3-Phenylsulfonylpropyl-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole

Following the procedure for example 52 except using the compound fromexample 56 as the sulfoxide and recrystalizing from hexane following thechromatography afforded the title compound as white solid. mp=109-110°.

Example 591-[3-(4-Morpholinyl)propyl]-4-(3-chlorophenyl)-5-(4-pyridyl)imidazole

a) 3-chlorophenyl-tolylthiomethylisocyanide

Following the procedure of example 1(a,b) except using3-chlorobenzaldehyde as the aldehyde component the title compound wasprepared.

b) 1-[3-(4-Morpholinyl)propyl]-4-(3-chlorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1(d) substituting the isocyanideprepared in the previous step the title compound was prepared. MS-DCINH₃=383 [M+H].

Example 601-[3-(4-Morpholinyl)propyl]-4-(3,4-dichlorophenyl)-5-(4-pyridyl)imidazole

Following the procedure of example 1(d) substituting the isocyanideprepared in Example 67(a) the title compound was prepared. mp=106°.

Example 614-[4-(4-Fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(pyrimid-2-one-4-yl)imidazole

a) 2-Methylthiopyrimidine-4-carboxaldehyde[3-(4-morpholinyl)propyl]imine

Following the procedure of example 1(c) except using2-methylthiopyrimidine-4-carboxaldehyde [Bredereck H. et al. Chem. Ber.1964, 3407] afforded the title compound as a yellow oil.

b)4-(4-Fluorophenyl)-1-[3-(4-morpholinyl)propyl]-5-(pyrimid-2-one-4-yl)imidazole

Concentrated aqueous ammonium hydroxide (2 mL) was added to4-(4-fluorophenyl)-5-[2-(methylsulfinyl)-4-pyrimidinyl]-1-[3-(4-morpholinyl)propyl]-imidazole(0.14g, 0.37 mmol) [prepared in Example 63] and the reaction mixture washeated to 150° C. for 18 h. After cooling to ambient temperature, theammonium hydroxide was decanted. The residue was purified by flashchromatography eluting successively with 4% and 10% methanol indichloromethane followed by successive elutions with mixtures of 90/10/1and 70/30/3 chloroform/methanol/concentrated ammonium hydroxide.Trituration with ether afforded the title compound as an off-white solid(0.035 g, 24%). ESMS (m/z): 384 (M⁺ +H).

Example 624-(4-Fluorophenyl)-5-[2-(methylthio)-4-pyrimidinyl]-1-[3-(4-morpholinyl)propyl]-imidazole

Following the procedure of 1(d) except using2-methylthiopyrimidine-4-carboxaldehyde [3-(4-morpholinyl)propyl]imine[prepared in Example 61(a)] afforded the title compound as a yelow oil.¹H NMR (CDCl₃) δ 8.31(d, J=7 Hz, 1H), 7.64(s,1H), 7.46 (dd, 2H), 7.05(t,J=8 Hz, 2H), 6.81(d, J=5 Hz, 1H), 4.42(t, J=7.5 Hz, 2H), 3.71(t, J=5 Hz,4H), 2.58(s, 3H), 2.37(brd. s, 4H), 2.27(t, J=6 Hz, 2H), 1.85(m, 2H).

Example 634-(4-Fluorophenyl)-5-[2-(methylsulfinyl)-4-pyrimidinyl]-1-[3-(4-morpholinyl)-propyl]imidazole

A solution of K₂S₂O₈ (0.20 g, 0.73 mmol) in water (5 mL) was added to4-(4-fluorophenyl)-5-[2-(methylthio)-4-pyrimidinyl]-1-[3-(4-morpholinyl)propyl]imidazole(0.20 g, 0.48 mmol) in glacial acetic acid (10 mL). After stirring atambient temperature for 72 h, the reaction mixture was poured intowater, neutralized with concentrated aqueous ammonium hydroxide andextracted four times with dichloromethane. The organic phases werecombined and evaporated. The residue was purified by flashchromatography eluting successively with 1%, 2%, 4% and 10% methanol indichloromethane to afford the title compound as a clear oil (0.15 g,73%). ¹H NMR (CDC₁₃) δ 8.57(d, J=7 Hz, 1H), 7.77(s,1H), 7.47 (dd, 2H),7.18(d, J=5 Hz, 1H) 7.09(t, J=9 Hz, 2H), 4.56(m, 2H), 3.72(t, J=5 Hz,4H), 3.00(s, 3H), 2.40(brd. s, 4H), 2.33(t, J=8 Hz, 2H), 1.94(m, 2H).

Example 64(E)-1-(1-Propenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole

a) Pyridine-4-carboxaldehyde (2-propenyl)imine

Pyridine-4-carboxaldehyde and 2-propenyl amine were reacted by theprocedure of example 1(c) to afford the title compound as a yellow oil.

b) (E)-1-(1-Propenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded a mixture of the title compound and1-(2-Propenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole.Chromatography of the mixture with 0-50% EtOAc in hexanes afforded thetitle compound (43%). mp=173.5-174.0.

Example 65 1-(2-Propenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole

Furthur chromatography of the mixture from example 64(b) afforded thetitle compound (54%). mp=116.0-117.0.

Example 665-[(2-N,N-Dimethylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-[3-(4-morpholinyl)-propyl]imidazole

Following the procedure of example 61(b) except using aqueousdimethylamine afforded the title compound as a yellow glass. ESMS (m/z):411 (M⁺ +H).

Example 671-[3-(4-Morpholinyl)propyl]-5-(4-pyridinyl)-4-[4-(trifluoromethyl)phenyl]imidazole

a) 4-trifluoromethylphenyl-tolylthiomethylisocyanide

Following the procedure of example 1(a,b) except using4-trifluoromethyl-benzaldehyde as the aldehyde component the titlecompound was prepared.

b)1-[3-(4-Morpholinyl)propyl]-5-(4-pyridinyl)-4-[4-(trifluoromethyl)-phenyl]imidazole

The imine prepared in Example 1(c) was reacted with the isocyanideprepared in the previous step using the procedure of example 1(d) toprepare the title compound. mp 133°.

Example 681-[3-(4-Morpholinyl)propyl]-5-(4-pyridinyl)-4-[3-(trifluoromethyl)phenyl]imidazole

a) 3-trifluoromethylphenyl-tolylthiomethylisocyanide

Following the procedure of example 1(a,b) except using3-trifluoromethyl-benzaldehyde as the aldehyde component the titlecompound was prepared.

b)1-[3-(4-Morpholinyl)propyl]-5-(4-pyridinyl)-4-[4-(trifluoromethyl)-phenyl]imidazole

The imine prepared in Example 1(c) was reacted with the isocyanideprepared in the previous step using the procedure of example 1(d) toprepare the title compound. ESMS=417 [M+H]

Example 691-(Cyclopropylmethyl)-4-(3,4-dichlorophenyl)-5-(4-pyridinyl)imidazole

a) 3,4-dichlorophenyl-tolylthiomethylisocyanide

Following the procedure of example 1(a,b) except using3,4-dichlorobenzaldehyde as the aldehyde component the title compoundwas prepared.

b) 1-(Cyclopropylmethyl)-4-(3,4-dichlorophenyl)-5-(4-pyridinyl)imidazole

Following the procedure of example 1(d) substituting the imine preparedin Example 27(a) and the isocyanide prepared in the previous step thetitle compound was prepared. mp=145.5°.

Example 701-(Cyclopropylmethyl)-4-(3-trifluoromethylphenyl)-5-(4-pyridinyl)imidazole

Following the procedure of Example 1(d) substituting the imine preparedin Example 27(a) and the isocyanide prepared Example 68(a) the titlecompound was prepared. mp=105.5°.

Example 711-(Cyclopropylmethyl)-4-(4-fluorophenyl)-5-(2-methylpyrid-4-yl)imidazole

a) 2-Methylpyridine-4-carboxaldehyde (cyclopropylmethyl)imine

Reaction of 4-formyl-2-methylpyridine [prepared in Example 33(a)] andcyclopropylmethyl amine by the procedure of example 1(c) affords thetitle compound as a yellow oil.

b)1-(Cyclopropylmethyl)-4-(4-fluorophenyl)-5-(2-methylpyrid-4-yl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound was as a whitesolid (62% from the 2-aminopyrimidine aldehyde). mp=141.0-141.5°.

Example 721-[3-(4-Morpholinyl)propyl]-5-(4-pyridinyl)-4-(3,5-bistrifluoromethylphenyl)-imidazole

a) 3,5-bistrifluoromethylphenyl-tolylthiomethylisocyanide

Following the procedure of example 1(a,b) except using3,5-bistrifluoromethyl-benzaldehyde as the aldehyde component the titlecompound was prepared.

b)1-[3-(4-Morpholinyl)propyl]-5-(4-pyridinyl)-4-(3,5-bistrifluoro-methylphenyl)imidazole

Following the procedure of example 1(d) substituting the imine preparedin Example 1(c) and the isocyanide prepared in the previous step thetitle compound was prepared. mp=136.5-137.5°.

Example 735-[4-(2-Aminopyrimidinyl)]-4-(4-fluorophenyl)-1-(2-carboxy-2,2-dimethylethyl)-imidazole

a) 2-Aminopyrimidine-4-carboxaldehyde (ethyl3-amino-2,2-dimethyl-propionate)imine

2-Aminopyrimidine-4-carboxaldehyde and ethyl3-amino-2,2-dimethyl-propionate, were reacted by the procedure ofexample 1(c) to afford the title compound as a yellow oil.

b)5-[4-(2-Aminopyrimidinyl)]-4-(4-fluorophenyl)-1-(2-carboxyethyl-2,2-dimethylpropyl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound as a white solid(11% from the amine).

c)5-[4-(2-Aminopyrimidinyl)]-4-(4-fluorophenyl)-1-(2-carboxy-2,2-dimethylethyl)imidazolelithium salt

The compound of example 73(c) was hydrolysed by the procedure of example37 to afford the title compound as the lithium salt; (67%). ES (+) MSm/e=356.

Example 741-(1-Formyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole

1-(1-Benzylpiperidin-4-yl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole(100 mg; prepared in Example 40) was dissolved in 10% formicacid/methanol under argon and palladium black (100 mg) mixed in 10%formic acid/methanol was added. The reaction was stirred under argon atroom temperature for sixteen hours. The reaction mixture was evaporatedand the residue mixed in H₂O/ethyl acetate and the pH taken to 10. Thelayers were separated and the aqueous phase extracted with ethylacetate. The combined organic layers were evaporated and the residue wasflash chromatographed (silica gel/methylene chloride/methanol) to yieldthe title compound, an off-white solid. ES (+) MS m/e=351 (MH⁺).

Example 755-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(1-methyl-4-piperidinyl)imidazole

a) 4-Amino-1-methylpiperidine

1-Methylpiperidin-4-one (4.22 g, 37 mmol) and an ice cold soln of 1N HClin Et₂O (37 mL, 37 mmol) were combined. Trituration followed byevaporation of the Et₂O at 23° under a stream of argon afforded thehydrochloride. MeOH (114 mL), anhydrous NH₄OAc (28.7, 373 mmol) and 3Amolecular sieves were added. Stirred 10 min and then NaCNBH₃ (2.33 g, 37mmol) was added, and the mixture was stirred for 1 h. Acidified to <pH 1with concentrated HCl and washed with Et₂O. The resulting mixture wasmade basic with 50% aq NaOH and extracted with EtOAc, dried (K₂CO₃), anddistilled (bp=55-60°, 15 mm) to afford 3.88 g (88%) of the titlecompound.

b) 2-Aminopyrimidine-4-carboxaldehyde (1-methylpiperidin-4-yl)imine

2-Aminopyrimidine-4-carboxaldehyde and the compound of the previous stepwere reacted by the procedure of example 1(c) to afford the titlecompound as a yellow oil.

b)5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl-1-(1-benzylpiperidin-4-yl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound afterpurification by chromatography on silica with 0-10% MeOH and 0-1% Et₃Nin CH₂Cl₂ followed by fractional preciptation from MeOH with Et₂O; as ayellow solid (20% from the amine). mp=235-237° (dec.).

Example 761-(2,2-Dimethyl-3-morpholin-4-yl)propyl-4-(4-fluorophenyl)-5-(2-Amino-4-pyrimidinyl)imidazole

a) N-(1-Amino-2,2-dimethylpropyl)morpholine

2,2-dimethyl-3-N-morpholinyl propionaldehyde (Cheney,L. L. J. Amer.Chem. Soc. 1951, 73, p685-686; 855 mg, 5.0 mmol) was dissolved in Et₂O(2 mL) and 1 N HCl in Et₂O (5 mL, 5 mmol) was added. Stirred 5 min andthe Et₂O was evaporated in a stream of Ar. The solid was dissolved inanhydrous MeOH (15 mL) followed by anhydrous NH₄OAc (3.85 g, 50 mmol),and 3A molecular sieves. Stirred 5 min and then NaCNBH₃ (0.314 g, 4.0mmoL) was added. Stirred 45 min and concd HCl was added til the reactionmixture was <pH 1. The MeOH was removed in vacuo and the residualmixture was dissolved in H₂O (15 mL) and extracted with Et₂O (25 mL).The aq phase was layered with another portion of Et₂O and made basic byaddition of 50% aq NaOH til>pH 10. Extraction with Et₂O (3×40 mL),drying (K₂CO₃) and concentration afforded the title compound (86%).

b) 2-Aminopyrimidine-4-carboxaldehyde[3-(4-Morpholinyl)-2,2-dimethylpropyl]imine

2-Aminopyrimidine-4-carboxaldehyde and the product of the previous stepwere reacted by the procedure of example 1(c) to afford the titlecompound as a yellow oil.

c)1-(2,2-Dimethyl-3-morpholin-4-yl)propyl-4-(4-fluorophenyl)-5-(2-Amino-4-pyrimidinyl)imidazole

Following the procedure of example 1(d) except using the compound of theprevious step as the imine afforded the title compound as a white solid(16% from the amine). mp=242-245° (dec.).

Example 77 4-(4-Fluorophenyl)-5-(4-pyridyl)-1-(2-acetoxyethyl)imidazole

500 mg of 4-(4-Fluorophenyl)-5-(4-pyridyl)imidazole was dried at 50° C.overnight in vacuo and added to a flask containing 20 ml of dried(sieve) dimethyl formamide (hereinafter DMF) and treated with NaH (at 0°C.), then stirred at room temperature, and dropwise with 2-acetoxyethylbromide. After three days, the mixture was poured into ice water,extracted into methyoene chloride, the organic phase washed with water,dried over sodium sulfate and stripped in vacuo. Flashed the residue onsilica using CH₂Cl₂-acetone (85:15) and eluting with increasing CH₃OHfrom 0 to 10%. Two major product fractions were obtained, the pure cutscombined to give a slower eluting fraction and a faster eluting isomer.These isomers were stripped and recrystallized from EtOAc-hexane to givethe minor isomer (slower moving) and the fast, major isomer (the titledcompound). NMR (250 mHz, CDCl₃) shows CH₂CH₂ as singlet at δ 4.1 ppm,very clean, H-ortho to F, triple t at 6.9 ppm. Cal'd C: 66.60, H: 4.86,N: 12.92; Found C: 67.10, 67.03 H: 5.07, 4.94 N: 13.08, 13.09. IR (nujolmull) shows 1740 cm⁻¹ (sharp, ester).

Example 785-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-N-morpholino-1-propyl)imidazol

a) 2-N-Methylaminopyrimidine-4-dimethylacetal

Sodium (3.27 g, 142 mmol) was dissolved in absolute ethanol (425 mL).1-Methylguanidine hydrochloride (15.5 g, 142 mmol) was added and theresulting slurry was stirred for about 10 min.1,1-Dimethoxy-2-oxo-4-dimethylamino-3-butene (142 mmol) dissolved inethanol (20 mL) was added and the mixture was stirred at reflux forabout 24 hours. The mixture was cooled and filtered. Ethanol wasevaporated and the resulting residue was triturated with hot EtOAc.EtOAc washings were combined and solvent was evaporated to afford thetitle compound (23.5 g, 91% yield) as a yellow oil. ¹H NMR (CDCl₃): δ8.35 (d, J=4.5 Hz, 1H), 6.74 (d, 1H), 5.10 (s, 1H), 3.40 (s, 6H), 3.00(d, 3H).

b) 2-N-Methylaminopyrimidine-4-carboxaldehyde

Following the procedure of Example 41 (b) except using the compound ofthe previous step (11.75 g, 64.6 mmol) afforded the title compound as ayellow foam (7.3 g, 82.7% yield). ¹H NMR (CDCl₃): δ 9.85 (s, J=4.5 Hz,1H), 8.52 (s, 1H), 7.03 (d, 1H), 5.52 (s, 1H), 3.10 (d, 3H).

c)5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-N-morpholino-1-propyl)imidazole

The compound of the previous step (5.0 g, 36.5 mmol) and4-(3-aminopropyl) morpholine (5.3 mL, 36.5 mmol) were stirred in CH₂Cl₂(180 mL). After about 16 h the mixture was cooled to 0° C. Added werethe compound of Example 1 (b) (11.3 g, 43.8 mmol) and TBD (8.4 g, 61.32mmol). The mixture was let stand for about 3 days at about 5° C. Theproduct filtered and triturated with hot EtOH to afford the titlecompound (6.06 g, 41.9% yield) as a pale yellow solid. mp=203-305° C. ¹HNMR (CDCl₃/MeOD): δ 8.01 (d, J=4.5 Hz, 1H), 7.60 (s, 1H), 7.37 (q, 2H),6.95 (t, 2H), 6.29 (d, 1H), 4.32 (s, 1H), 3.63 (t, 4H), 3.57 (m, 2H),2.95 (s, 3H), 2.33 (m, 4H), 2.23 (t, 2H), 1.82 (t, 2H).

Example 795-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-N-methylpiperidine)imidazole

a)5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-N-methylpiperidine)imidazole

The compounds of Example 75 (a) (4.25 g, 37.2 mmol) and Example 78 (b)as prepared above (5.1 g, 37.2 mmol) were combined in CH₂Cl₂ (150 mL).This mixture was stirred for about 16 hours at room temperature, andcooled to 0° C. The compound of Example 1(b) and TBD were added and theresulting mixture was stirred at room temperature for about 3 days. Themixture was poured directly on a silica gel column and was purified byflash chromatography eluting with 0%-5% MeOH/CH₂Cl₂. The resulting oilwas washed in acetone/hexane and the precipitate was filtered, washingwith acetone to afford the title compound (1.36 g, 10% yield) as a paleyellow solid. mp=209-210° C. ¹H NMR (CDCl₃): δ 8.16 (d, J=4.5 Hz, 1H),7.77 (s, 1H), 7.45 (q, 2H), 6.98 (t, 2H), 6.41 (d, 1H), 5.20 (d, 1H),4.66 (s,l H), 3.05, (d, 3H), 2.98 (d, 2H), 2.32 (s, 3H), 2.14 (m, 2H),2.01 (m, 4H).

In methods analagous to those described above the following compound maybe prepared:

Example 805-[4-(2-N-Methylamino)pyrimidinyl)}-4-(4-fluorophenyl)-1-(4-piperidine)imidazole

In an alternative synthesis the title compound may be prepared asfollows:

5-[4-(2-N-Methylamino)pyrimidinyl}-4-(4-fluorophenyl)-1-(4-piperidine)-imidazole

a)5-[4-(2-N-Methylamino)pyrimidinyl}-4-(4-fluorophenyl)-1-(4-N-Boc-piperidine)-imidazole

A solution of 2-methylamino-4-pyrimidine carboxaldehyde (2.47 g, 17.99mmol) and t-butyl 4-amino-1-piperidine carboxylate (as described inexample 46 (a)), (3.96 g, 19.79 mmol) in 36 mL of DMF was stirred atabout 25° C. for about 5 to 6 h. After cooling to about 0° C., theisonitrile of step (b), Example 85 (b) (6.24 g, 21.60 mmol) and powderedK₂CO₃ (2.98 g, 21.60 mmol) were added. The solution was gradually warmedto about 25° C. over about 3 h. After about 16 h, 100 mL of H₂O wasadded and the resulting mixture was filtered, washed with 20 mL of H₂Oand 50 mL of t-butyl methyl ether. After drying, 6.85 g (84%) of thetitle product was obtained as a white powder. ¹H NMR (300 MHz, CDCl₃) δ8.15 (1H, d, J=5.0 Hz), 7.72 (1H, s), 7.45 (2H, m), 6.99 (2H, t, J=8.7Hz), 6.40 (1H, d, J=5.1 Hz), 5.20 (1H, m), 4.80 (1H, m), 4.28 (2H, m),3.03 (3H, d, J=5.0 Hz), 2.76 (2H, t, J=12.2 Hz), 2.17 (2H, d, J=12.2Hz), 1.86 (2H, dq, J=4.3, 12.4 Hz), 1.48 (9H, s).

b)5-[4-(2-N-Methylamino)pyrimidinyl}-4-(4-fluorophenyl)-1-(4-piperidine)-imidazole

To a stirred suspension of the N-BOC derivative of Step (a) above, (31g, 68 mmoles) in ethyl acetate (310 mL, 10 volumes) was added 3N aqueousHCl (160 mL, 476 mmoles, 7 equiv.) at 25° C. The resulting cloudy yellowsolution was stirred at 25° C. for 2 hours. The pH of the reactionmixture was adjusted to 12-13 by the slow addition of 50% aqueous NaOH.The phases were separated and the aqueous was extracted twice withmethylene chloride (200 mL each). The combined organic extracts werewashed with water, dried over MgSO₄ and rotary evaporated to dryness.The resulting light-yellow residue was slurried in hot ethylacetate/methylene chloride (200 mL of a 9:1 mixture) and allowed to coolto 25° C. The product was collected by suction filtration and rinsedwith ethyl acetate (25 mL). The white solid was dried to a constantweight at 50° C./<1 mm to give 19 g (54 mmoles) of the desired titledproduct, affording a 79% yield. ¹H NMR (300 MHz, CDCl₃) δ 8.15 (1H, d,J=5.0 Hz), 7.77 (1H, s), 7.45 (2H, m), 6.99 (2H, t, J=8.7 Hz), 6.40 (1H,d, J=5.1 Hz), 5.23 (1H, m), 4.76 (1H, m), 3.22 (2H, d, J=12.4 Hz), 3.05(3H, d, J=5.1 Hz), 2.67 (2H, dt, J=2.0, 12.3 Hz), 2.16 (2H, d, J=11.8Hz), 1.86 (2H, dq, J=3.9, 12.2 Hz).

Example 815-[(2-Ethlamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazole

a) 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal

Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) andN,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) werecombined in a 500 mL flask and heated at 100° C. After 4.5 h the flaskwas removed from the heat, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt.% solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added andheating was continued at 65° C. After 18 h the solution was cooled to25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic).After 3 h, the solution was diluted with 250 mL of H₂O and extractedwith EtOAc (3×100 mL). The organics were combined, dried over Na₂SO₄ andconcentrated to give the title compound (26.8 g, 93%) as a brown oil.

b) 2-Methylthiopyrimidine-4-carboxaldehyde

2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal (30.0 g, 150mmol) was dissolved in 300 mL of glacial AcOH and 3 mL of conc. H₂SO₄and heated at 80° C. After 10 h, the solution was cooled to 25° C. andthe AcOH was removed in vacuo, leaving a brown oil residue. This residuewas diluted in 200 mL of CH₂Cl₂ and washed with saturated NaHCO₃ (3×50mL), H₂O (50 mL) and brine (50 mL). The organics were dried over MgSO₄and concentrated to yield 22.1 g (96%) of the title compound as a brownoil.

c) 2-Methylthiopyrimidine-4-carboxaldehyde (1-methylpiperdin-4-yl)imine

2-Methylthiopyrimidine-4-carboxaldehyde (5.6 g, 36 mmol) and4-amino-1-methylpiperidine dihydrochloride (6.73 g, 36 mmol) weredissolved in 200 mL of CH₂Cl₂ and NaHCO₃ (10.6 g, 126 mmol) was added.After 20 h, the solution was filtered and concentrated to yield 8.9 g(98%) of the title compound as a brown oil.

d)4-(Fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methylthio-4-pyrimidinyl)imidazole

t-BuNH₂ (3.90 mL, 37.08 mmol) was added rapidly to a solution of2-methylthiopyrimidine-4-carboxaldehyde (1-methylpiperdin-4-yl)imine(3.71 g, 14.83 mmol) and 4-fluorophenyl-tosylmethylisocyanide (5.15 g,17.8 mmol) dissolved in 50 mL of DME at 25° C. After 14 h, the solutionwas diluted with 50 mL of EtOAc and washed with 50 mL of sat. NaHCO₃ and25 mL of brine. The organics were dried over Na₂SO₄ and concentrated.Crystallization from the crude residue using EtOAc/hexanes yielded 2.85g (50%) of the product as a light brown crystal. ¹H NMR (CDCl₃, 300 MHz)δ 8.31 (1H, d, J=5.1 Hz), 7.78 (1H, s), 7.40 (2H, m), 6.99 (2H, t, J=8.7Hz), 6.76 (1H, d, J=5.2 Hz), 4.67 (1H, m), 2.97 (2H, m), 2.58 (3H, s),2.31 (3H, s), 2.06 (6H, m).

e)4-(Fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methysulfinyl-4-pyrimidinyl)imidazole

Potassium persulfate (3.2 g, 7.0 mmol) in water (75 mL) was added to asolution of4-(fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methylthio-4-pyrimidinyl)imidazole(2.7 g, 7.0 mmol) in glacial AcOH (150 mL). After stirring at ambienttemperature for 72 h, the reaction mixture was neutralized by theportion-wise addition of concentrated aqueous NH₄OH and extracted withCH₂Cl₂. The organic extract was washed with brine, dried (MgSO₄) andconcentrated. The residue was triturated with ethyl ether to afford thetitle compound as an off-white solid; yield 2.3 g (83%).

f)5-[(2-Ethylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazole

4-(Fluorophenyl)-1-(methyl-4-piperidinyl)-5-(2-methysulfinyl-4-pyrimidinyl)imidazole(0.25 g, 0.65 mmol) and 70% aqueous ethylamine (2.5 mL) were heated to120° C. in a sealed reaction vessel for 18 h. After cooling to ambienttemperature, volatiles were evaporated and the residue was trituratedwith ethyl ether to afford the title compound as a white solid; yield0.13 g (53%): ES (+) MS m/e=381 (MH⁺).

Example 824-(4-Fluorophenyl)-5-[2-(isopropyl)aminopyrimidiny-4-yl]-1-(1-methylpiperdin-4-yl)imidazole

Following the procedure of example 81, step (f) except substitutingisopropylamine afforded the title compound as a tan solid in 20% yield:ES (+) MS m/e=395 (MH⁺).

Example 835-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(1-methyl-4-piperdinyl)imidazole

a) 2-Acetamidopyrimidine-4-carboxaldehyde monomethyl monoacetoxy acetal

A mixture of 2-aminopyrimidine-4-carboxaldehyde dimethyl acetal (9.0 g,53 mmol) and acetic anhydride (25 mL) was heated to 60° for 18 h.Concetrated H₂SO₄ (10 drops) was added and the solution was heated to100° for 10 h. After cooling to ambient temperature, the volatiles wereevaporated and the residue was vacuum filtered through a pad of silicagel eluting with 4% MeOH in CH₂Cl₂. Evaporation of the filtrate followedby trituration of the residue with ether afforded the title compound asa white solid; yield 8.6 g (68%).

b) 2-Acetamidopyrimidine-4-carboxaldehyde

Sodium methoxide (0.056 g, 1.0 mmol) was added to a solution of2-acetamidopyrimidine-4-carboxaldehyde monomethyl monoacetoxy acetal(5.0 g, 21 mmol) in MeOH (25 mL) at ambient temperature. After stirringat this temperature for 3 h, the reaction mixture was neutralized byaddition of 3N HCl. The resulting solution was concentrated and theresidue was treated with CH₂Cl₂. Remaining solids were removed byfiltration and the solvent was evaporated to afford the title compoundas a yellow solid; yield 3.2 g (92%).

c) 2-Acetamidopyrimidine-4-carboxaldehyde (1-methylpiperdine-4-yl)imine

Following the procedure of example 75 (b) except substituting2-acetamidopyrimidine-4-carboxaldehyde afforded the title compound asoff-white solid in 75% yield.

d)5-(2-Acetamido-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(1-methyl-4-piperdinyl)imidazole

Following the procedure of example 81 (d) except substituting2-acetamidopyrimidine-4-carboxaldehyde (1-methylpiperdine-4-yl)imineafforded the title compound as yellow solid in 51% yield.

e)5-(2-Amino-4-pyrimidinyl)-4-4(4-fluorophenyl)-1-(1-methyl-4-piperdinyl)imidazole

A solution of5-(2-acetamido-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(1-methyl-4-piperdinyl)imidazole(4.0 g, 0.010 mol) in 40 mL of 3N HCl was heated to 75° C. for 18 h.After cooling to ambient temperature, the reaction mixture wasneutralized with solid sodium hydrogen carbonate. The resultingprecipitate was isolated by filtration, washed with water and air driedto afford the title compound as a white solid in qualitative yield.

Example 845-(2-Acetamido-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-N-morpholino-1-propyl)imidazole

A solution of5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-N-morpholino-1-propyl)imidazole(0.50 g, 1.3 mmol) in acetic anhydride (10 mL) was heated to reflux for18 h. After cooling to ambient temperature, excess acetic anhydride wasevaporated and the residue was partitioned between saturated aqueousNaHCO₃ and ethyl acetate. The layers were separated and the organicphase was concentrated. The residue was dissolved in MeOH (10 mL) and2.5N NaOH (1 mL) was added. After stirring at ambient temperature for 2h, the solution was partially evaporated and the resulting precipitatewas collected by filtration, washed with water and air-dried to affordthe title compound as a white solid; yield 0.28 g (51%): ES (+) MSm/e=425 (MH⁺).

Example 85

a) α-(p-Toluenesulfonyl)-4-fluorobenzylformamide

To a stirred solution of 4-fluorobenzaldehyde (124 g, 979 mmoles) inacetonitrile (620 mL, 5 volumes) and toluene (620 mL, 5 volumes) wasadded formamide (110 g, 2.45 moles, 2.5 equiv.) followed bychlorotrimethylsilane (119 g, 1.07 moles, 1.1 equiv.). The reaction washeated at 50° C. under nitrogen for 5 hours. To the resulting whiteslurry was added p-toluenesulfinic acid (230 g, 1.47 moles, 1.5 equiv.)and the reaction was heated at 50° C. for an additional 5 hours thencooled to ambient temperature. Methanol (250 mL) and t-butyl methylether (620 mL) were added. After 15 minutes the reaction was poured intowater (3 L) pre-cooled to 0° C. After stirring for 30 minutes at 0° C.,the product was collected by suction filtration and rinsed with t-butylmethyl ether (250 mL). The product, a white, crystalline solid, wasdried to a constant weight at 40° C./<1 mm Hg to afford 270 g (879mmoles) of desired product (90% yield). ¹H NMR (300 MHz, CD₃CN) δ 7.99(1H, s), 7.92 (1H, m), 7.71 (2H, d, J=8.3 Hz), 7.49 (2H, dd, J=5.3, 8.8Hz), 7.39 (2H, d, J=8.1 Hz), 7.16 (2H, t, J=8.8 Hz), 6.31 (1H, d, J=10.6Hz), 2.42 (3H, s).

b) α-(p-Toluenesulfonyl)-4-fluorobenzylisonitrile

A stirred suspension of α-(p-toluenesulfonyl)-4-fluorobenzylformamideproduced in step (a) above, (100 g, 325 mmoles) in THF (650 mL, 6.5volumes) was cooled to 0° C. and POCl₃ (46 mL, 487 mmoles, 1.5 equiv.)was added. A 1° C. exotherm was observed. After 15 minutes at 0° C., thewhite slurry was cooled to −5° C. Triethylamine (166 g, 1.62 moles, 5equiv.) was added dropwise to the slurry over 45 minutes at such a rateto keep the reaction temperature below 0° C. but above −5° C. Cautionshould be exercised at the beginning of the addition because thereaction has a tendency to exotherm quickly. After complete addition,the yellow slurry was stirred for 30 minutes at 0° C. The reactionslurry has a tendency to darken during the stirring period. The reactionwas poured into a mixture of saturated aqueous sodium bicarbonate (1 L)and ethyl acetate (1 L), both pre-cooled to 0° C. The organic phase wassubsequently washed with water followed by brine. The organic phase wasconcentrated under vacuum via rotary evaporation until about 10% of theinitial volume remained. 1-Propanol (200 mL) was added and concentratedagain under vacuum at 35° C. until about 10% of the initial volumeremained. This process was repeated with fresh 1-propanol (200 mL). Afine, yellow precipitate was observed. The precipitate was cooled to 0°C. and the product was collected by suction filtration and rinsed with1-propanol (50 mL). The off-white solid was dried to a constant weightat 40° C./<1 mm to give 65.7 g (227 mmoles) of desired product,affording a 70% yield. ¹H NMR (300 MHz, CDCl₃) δ 7.62 (2H, d, J=6.7 Hz),7.46 (4H, m), 7.08 (2H, t, J=8.6 Hz), 5.62 (1H, s), 2.46 (3H, s).

Example 865-(2-Acetamido-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(1-methyl-4-piperidinyl)-imidazole

To a solution of the 2-acetyamido pyrimidinyl-4-carboxaldehyde (0.84 g,5.08 mmol) and 1-methylpiperidin-4-yl-amino dihydrochloride salt (1.04g, 5.59 mmol) in 21 mL of DMF was added powdered K₂CO₃ (1.54 g, 11.2mmol). After approx 6 h, theα-(p-Toluenesulfonyl)-4-fluorobenzylisonitrile, produced in step (b)Example 85 above, (1.76 g, 6. 10 mmol) and powdered K₂CO₃ (0.84 g, 6.10mmo) were added and the sides of the flask rinsed with 5 mL of DMF.After 16 h, 300 mL of H₂O were added to the reaction mixture and thesolution was extracted with EtOAc (3×100 mL). The combined organics werewashed with H₂O (3×50 mL), dried over Na₂SO₄ and concentrated. The puretitle compound (0.75 g, 38%) was recrystallized from EtOAc as a paleyellow crystal. ¹H NMR (300 MHz, CDCl₃) δ 8.71 (1H, s), 8.39 (1H, d,J=5.2 Hz), 7.81 (1H, s), 7.39 (2H, m), 7.13 (2H, t, 3J 8.7 Hz), 6.81(1H, d, J=5.2 Hz), 4.88 (1H, m), 2.94 (2H, d, J=10.1 Hz), 2.47 (3H, s),2.32 (3H, s), 2.07 (6H, m).

Example 875-[4-(2-N-Methylthioamino)pyrimidinyl}-4-(4-fluorophenyl)-1-(4-piperidine)imidazole

To a solution of the 2-methylthio amino-4-pyrimidine carboxaldehyde (3.4g, 22.07 mmol) and 4-amino-1-methyl piperidine dihydrochioride salt(4.54 g, 24.3 mmol) in 44 mL of DMF was added K₂CO₃ (7.02 g, 50.8 mmol).After about 6 h, the solution was cooled to about 0° C. and theisonitrile of Example 85 step (b) (7.68 g, 26.5 mmol) and K₂CO₃ (3.57 g,25.38 mmol) were added and stiffed with gradual warming to about 25° C.After about 16 h, the reaction mixture was diluted with 200 mL of EtOAcand washed with 200 mL of H₂O. The aqueous layer was extracted withEtOAc (2×100 mL) and the combined organics were washed with H₂O (3×100mL). The organics were dried over Na₂SO₄ and concentrated and the titledproduct was recrystallized from EtOAc/Hex to give 5.12 g (61%) of a paleyellow crystal. ¹H NMR (300 MHz, CDCl₃) δ 8.33 (1H, d, J=5.3 Hz), 7.79(1H, s), 7.41 (2H, m), 7.01 (2H, t, J=8.7 Hz), 6.77 (2H, d, J=5.2 Hz),4.68 (1H, m), 2.98 (2H, m), 2.59 (3H, s), 2.32 (3H, s), 2.07 (6H, m).

Example 885-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-N-methylpiperidine)imidazole

To a solution of the 2-methylamino-4-pyrimidine carboxaldehyde (2.79 g,20.37 mmol) and 4-amino-1-methyl piperidine dihydrochloride salt (4.19g, 22.41 mmol) in 41 mL of DMF was added powdered K₂CO₃ (6.19 g, 44.82mmol). The mixture was stired at room temperature for about 6 h. Thesolution was cooled to about 0° C. and the isonitrile of Example 85,step (b) (7.07 g, 24.44 mmol) and powdered K₂CO₃ (3.10 g, 22.41 mmol)were added. Stir at about 0° C. for about 3 h, then slowly warm to roomtemperature over about 2 h. Add 100 mL of H₂O and stir for about 15 min.Filter the solution and wash with 50 mL of H₂O and 50 mL of TBME. Afterdrying, 5.56 g (74%) of the titled compound was isolated as an off-whitepowder. ¹H NMR (300 MHz, CDCl₃) δ 8.15 (1H, d, J=4.9 Hz), 7.76 (1H, s),7.45 (2H, m), 6.99 (2H, t, J=8.7 Hz), 6.40 (1H, d, J=5.1 Hz), 5.29 (1H,m), 4.65 (1H, br s), 3.04 (3H, d, J=5.1 Hz), 2.97 (2H, m), 2.31 (3H, s),2.13-1.98 (6H, m).

Example 895-[4-(2-Aminopyrimidinyl)]-4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidinyl)imidazole

a) 2-Aminopyrimidine-4-carboxaldehyde 4-(2,2,6,6-tetramethylpiperidinyl)imine

The compound of example 41(b) (0.752 g, 6.1 mmol),4-Amino-2,2,6,6-tetramethylpiperidine (1.00 g, 6.42 g), CH₂Cl₂ (90 mL),and CH₃OH (1 mL) were combined, stirred overnight and concentrated toafford the title compound as a yellow solid.

b)5-[4-(2-amino)pyrimidinyl}-4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidinyl)imidazole

The product of example 89 (a) the product of example 79 (b) (1.86 g,6.42 mmol), K₂CO₃ (0.842 g, 6.1 mmol), and DMF (12 mL), were combinedand stirred for 3 days. Poured into H₂O (25 mL) and extracted with EtOAc(4×25 mL) dried (Na₂SO₄) and concentrated to an oil. Flashchromatography (0-10% MeOH in CH₂Cl₂) afforded 0.837 g (35%) of thetitle compound. mp=227-230 (dec).

Example 90

In methods analogous to those described above except using the compoundof example 78 (b) as the aldehyde precursor to the imine the followingcompound may be prepared:

5-[4-(2-N-Methylamino-4-pyrimidinyl)]-4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidine)imidazole

mp=184-185.

In methods analogous to those described in example 1 except using theproduct of example of example 41 (b) or the product of example 78 (b) asthe aldehyde and the appropriate amine to afford the imine intermediate,the following compounds may be prepared:

Example 915-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-thiopyranyl)imidazole

mp=228-230.

Example 925-(2-Amino4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-pyranyl)imidazole

mp=222-223.

Example 935-(2-Methylamino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(2-cyanoethyl)imidazole

mp=193-194.

In methods analogous to those described in example 14 except using theproduct of example of example 91 as starting material, the followingcompound may be prepared:

Example 945-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-sulfinylpyranyl)imidazole

mp=255-265 (dec).

Example 955-(2-Amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(tetrahydro-4-sulfonylpyranylimidazole

The product of example 91 (213 mg, 0.6 mmol), CH₂Cl₂ (2.25 mL), CH₃OH(0.75 mL), and TFA (92 mL, 1.2 mmol) were cooled to 4° and MCPBA (ca.80%) (387 mg) was added, warmed to 23°, over 20 min, poured into EtOAc(50 mL), and washed with 5% aq Na₂CO₃, dried (Na₂SO₄), concentrated,filtered through a plug of silica (0-4% MeOH), afforded pure5-(2-amino-4-pyrimidinyl}-4-(4-fluorophenyl)-1-(tetrahydro-4-sulfonylpyranyl)imidazole(SB 226880) (80 mg, 34%). mp=228-230.

In methods analogous to those described in example 80 except using1-(2,2,2-trifluoroethyl)-4-aminopiperidine as the appropriate amine toafford the imine intermediate, the following compound may be prepared:

Example 965-(2-Methylamino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl-4-piperidinyl)imidazole

mp=189-191.

Example 975-(2-Amino-4-pyrimidinyl}-4-(4-fluorophenyl)-1-(trifluoroacetyl-4-piperidinyl)imidazole

The product of example 46 (c) (500 mg, 1.12 mmol)was suspended in CH₂Cl₂(50 mL), and Et₃N (585 mL, 4.2 mmol)was added and after 30 sectrifluoroacetic anhydride (160 mL, 1.12 mmol) was added. After 1 h theinsoluble material was filtered off and the filtrate was concentrated.The resulting white powder was filtered through a plug of silica (1-2%CH₃OH in CH₂Cl₂ to afford 350 mg (72%) of the title compound.mp=249-250.

In methods analogous to those described in example 1 to 97 the followingcompounds may be prepared:

Example 98 5-(4-Pyridyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole

m.p. 185-187.0° C.; and

Example 99 5-(4-Pyridyl)-4-(4-fluorophenyl)-1-(1-t-butoxycarbonyl-4-piperidinyl) imidazole Example 100 2-thiomethylpyrimidinealdehyde

2-thiomethylpyrimidine acetal (30.0 g, 150 mmol) was dissolved in 300 mlof concentrated H₂SO₄ and heated to 70-80° C. The reaction was monitoredon GC/MS. After about 3.5 hours, the starting material was completelyconsumed and the reaction was cooled to 25° C.and AcOH was removed invacuo, leaving a brown oil residue. This residue was dilued in 200 ml ofCH₂Cl₂ and NaHCO₃ (3×50 ml), H₂O and brine (50 ml). The organics weredried over MgSO₄ and concentrated to yield 22.1 g (96%) of a brown oilwhich was pure by NMR.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe are can, using the preceding description; utilize the presentinvention to its fullest extent. Therefore the Examples herein are to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

What is claimed is:
 1. A process for making 2-thiomethylpyrimidinealdehyde which process comprises reacting a compound of the formula:

with acetic acid and a catalytic amount of concentrated sulfuric acid.